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REPORT OF THE

NATIONAL LEVEL COMMITTEE OF EXPERTS

“TO REVIEW

The State investigation reports and to investigate the Adverse Events following

Immunization (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

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Preface Japanese encephalitis has been plaguing the country over several

decades. Since its discovery in the North Arcot district (now bifurcated into

Vellore and Tiruvannamalai districts) in Tamil Nadu in 1955, its prevalence

spread to neighboring south and southwest Karnataka and south and east-

central Andhra Pradesh in the 1960s, to West Bengal, Assam and nearby

regions in the early 1970s and to Uttar Pradesh in late 1970s, and finally to

central and south western parts of India – Maharashtra, Goa and Kerala in the

1990s.

Considerable scientific investigations on its vector identification and vector

biology and bionomics, host species, human risk factors of disease,

epidemiology, virology, diagnostic parameters, reagent-development and field

application, and laboratory work towards vaccine development have been

conducted under the leadership of the Indian Council of Medical Research. Yet,

a comprehensive plan for JE control was not made on account of various

reasons.

With assistance from Japan India established a vaccine manufacturing

unit at Central research Institute Kasauli. However, the vaccine, made in infant

mouse brain did not become widely accepted or popular.

In the 1990s the Chinese live attenuated JE virus vaccine became known

to the scientific world and since then its safety and efficacy had been discussed

in 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 and

all assessments were essentially positive. Consequently it was registered in

India and procured in large quantity. The intention was to begin administering the

vaccine in high risk areas prior to the next annual season of JE. In 2006 May,

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June and July it was used in mass campaigns in 11 districts in 4 States. In one

State (Assam) cases of JE had already started to occur when vaccine became

available. After discussing the pros and cons of vaccination, it was decided to

introduce JE vaccine in Assam also, for the benefit of children not yet infected.

All vaccines may cause some unwanted reactions in some children. All

licensed vaccines have gone through safety assessments, yet, it is wise and

essential to monitor adverse events following vaccination in order to detect any

unknown adverse effects that may arise due to the vaccine. Thus, the four

States that distributed and inoculated the JE vaccine in children had conducted

adverse events monitoring procedures. Such events were brought to medical

attention.

From such data one must differentiate background noise from events due

to the vaccination and also differentiate minor or inconsequential reactions from

serious and life-threatening reactions. The term ‘adverse events following

immunization’ (AEFI) denotes events within a selected time interval after

vaccination, but such sequence and temporal association does not necessarily

mean causal relationship. The data base on AEFI consisted of 533 specific

children with illnesses that were reported within two weeks of vaccination. Among

them 65 were considered severe, among which 22 children had died. The task

of the Committee was to examine these cases to differentiate causal association

from temporal but coincidental association. The findings of this examination of

evidences 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 of

assistance to the GoI in the nation’s efforts in containing the problem of JE. This

report is divided into chapters and several of them will provide comprehensive

background 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 of

the Immunization Division under the Ministry of Health and Family Welfare and of

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

Team leader

5 October, 2006

t

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Executive summary

The Committee has scrutinized the details of all cases of Adverse Events

Following Immunization (AEFI) with SA-14-14-2 JE Vaccine that were reported in

the 11 districts of the 4 States in which 9.308 million children were given the live

attenuated Japanese encephalitis vaccine. A total of 533 children with AEFI

occurring within 2 weeks of vaccination were reported. Among them 438 children

had very minor symptoms and were seen in the outpatient clinic and treated with

symptomatic treatment as needed. Of the remaining 65 children 43 were

hospitalized and 21 among them died. One more child died on the way to the

hospital. Thus 22 children died.

The frequency of 22 deaths among 9.308 million vaccinated children aged

1-15 years works out as 0.236 / 100000 (0.00024%). Based on the population

(Census 2001), annual growth rate, estimated number of children and age

specific death rates we arrived at the probable frequency of death in 1-14 year

age 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 JE

Vaccine) has not exceeded this background rate. Thus there seems to be no

prima facie evidence that AEFI has contributed any excess mortality.

Two prominent clusters of illnesses and a number of miscellaneous ones

constituted the 65 “serious” events – 43 hospitalized and recovered and 22 died.

One cluster was obviously acute encephalitis, in Assam, where JE had already

started as an outbreak. We conclude that the cases of encephalitis reported as

were causally unrelated to JE vaccine. Epidemiologically, JE vaccine campaign

did not induce any spurt of the number cases – indeed, following vaccination

cases rapidly declined.

The second cluster of cases was due to an acute encephalopathy

syndrome, a disease that occurs among young children in UP. It is characterized

by sudden onset, rapid progression and high case-fatality. Such cases have

been occurring annually in different parts of UP and occasionally in neighboring

States as well. We do not know what causes such illnesses and without an

understanding of specific case criteria and etiology, it is not possible to ask or

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answer retrospectively whether JE vaccination (SA-14-14-2 JE Vaccine) has in

any way contributed to its triggering in predisposed children. We do not consider

that the available evidence suggests causal relationship with JE vaccine (SA-14-

14-2). The following are the committee’s recommendations to the Government of

India. .

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.

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Chapter I The Establishment of the Committee

A National level committee of experts was formed on 13th July 2006 “to review State

investigation reports & to investigate the Adverse Events following Immunization (AEFI)

following vaccination with live attenuated SA-14-14-2 vaccine against Japanese

Encephalitis (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) – Coordinator

Terms 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 license

purchase and import the live attenuated JE vaccine from China, after the due processes

of procedures. Against the background of large outbreak of JE in eastern Uttar Pradesh

in 2005 and the continued endemicity of JE in other States, the vaccine was given to

children in 11 selected high risk districts in 4 States in mass campaigns, during mid-May

through July. The adverse events following vaccination form the data base for this

committee 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.

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Chapter II Japanese Encephalitis in India

Introduction Japanese 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 mortality as well as disability in surviving children, in most of Asia. The disease affects primarily children under the age of fifteen, leaving up to 70 percent of those who develop illness either dead or with long-term neurological disabilities. JE has spread beyond its early domain, spreading as far south as northern Australia and as far west as Pakistan from its early geographic detection in Japan in the late 19th century. To date JE has not appeared 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 programs

in South East Asian countries. Following a review of JE control programs in all countries endemic for JE it was found that JE control efforts with vector control alone was without the 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 not recommended as an effective strategy for JE control, although integrated vector control for 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 Pondichery

1 Bi Regional JE Conference, March, 2005

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• 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 since 1978. In the last decade cases have been reported almost annually in 12 States and UTs. The surveillance system is not complete or comprehensive. However, the numbers of clinically diagnosed cases are cumulated in Government hospitals, forming the 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. No.

Affected States / Union Territories 2002 2003 2004 2005

C D C D C D C D1 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

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Prevention and control Prevention 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 under the integrated scheme for National Vector Borne Disease Control Programme (NVBDCP), as approved by the Cabinet Committee on Economic Affairs (CCEA) on October 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 JE

Epidemiology of JE in India

Setting JE is a disease predominantly of the rural population, on account of the vector prevalence and densities. Culicines breed mainly in irrigated paddy fields and similar surface bodies of water and they are more in rural than in urban locales. However cases have been reported from urban areas like Lucknow and Bangalore in recent past.2 In planning control initiatives it should also be considered that in most of the endemic districts in states like Uttar Pradesh and Bihar the demarcation between urban and rural population is unclear particularly in the context of lack of quality data from surveillance. JE outbreaks have also been reported in peri-urban areas.

Age group Clinical encephalitis occurs in one in 300-500 infected individuals. Silent infection confers life-long immunity. In southern India, JE almost exclusively affects children below 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 The reason is epidemiologically explainable. In endemic areas adults are mostly immune on account of past infection, whereas in newly introduced areas both children and adults are susceptible. Over time the new locations become endemic and cases occur exclusively 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 age distribution, this information could be used for planning purposes in that state. E.g. review of surveillance data for the last decade (1990-2000) had helped planning immunization in the age group of 2-12 years in AP

2 In another instance 58 hospitalized children (0-15 year) suffering from AES (Acute Encephalitis Syndrome) were investigated between July 2001 and February 2002 in the known endemic district of Cuddalore in Tamil Nadu. Spatial clusters of cases were evident in three different municipalities’ viz. Chidambaram, Virudhachalam and Thittakudi.2 3 ICMR report on Japanese Encephalitis

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Seasonality Transmission of JE typically begins in Assam in March through April with peaks in later months. As one goes south, onset of the disease occurs in later months. The outbreak of JE in Kerala in 1996 was also in the first quarter of the year. Mosquito breeding is impeded by heavy rainfall although vector abundance, and hence high rates of virus transmission, is associated with rainfall. It is the rainfall pattern, rather than total rainfall, which is more important. Mosquitogenic conditions are created if water accumulates for long periods. Flooding and receding water lines in the Brahmaputra river basin in northeast India create enormous pools and puddles leading to high mosquitogenic conditions that often do not correlate with rainfall. Canal fed ditches and paddy fields are another breeding source of mosquitoes outside the monsoon season, and outbreaks occur regularly in predominantly canal-irrigated regions like Mandya district of Karnataka. In northern India, the shift from dry land wheat cultivation to wet paddy cultivation using ground and canal water emerged as an important risk factor for high mosquitogenic conditions leading to outbreaks of JE. Month 1 2 3 4 5 6 7 8 9 10 11 12 As √ WB √ UP √ √ √ √ √ √ √ AP √ √ √ √ √ Ka Mandya √ √ √ √ √ TN √ √ √ √ Goa √ √ √ √ √ √ Vectors Culex tritaeniorhynchus and Cx. vishnui are the principal vectors of JE in India. The virus has 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 unvaccinated male child between the ages of 1 and 15 years living in a rural/peri-urban area with paddy 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 in India indicates that all children in the age group 1-15 years living in endemic districts must be considered to be at risk of JE

4 Soman RS, Rodrigues FM, Guttikar SN, et al. Experimental viraemia and transmission of Japanese encephalitis virus by mosquitoes in ardeid birds. Indian Journal of Medical Research. 1977;66:709–718.

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JE Control Strategy: The goal in JE control in India is to reduce incidence of JE by more than 50% by 2010.5

The three “pillars” of JE control will be utilized. In addition, although measures of vector control have a limited role in controlling JE, integrated vector control (NVBDCP) for all vector-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 vector borne 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 Strategy India has a surveillance system based on public sector institutions. In order to support immunization, particularly to monitor the success of immunization, the system will need to be further strengthened. Effective surveillance with laboratory support when needed will help to both monitor the impact of immunization as well as identify new areas of transmission. Reporting should regularly include age of patient and district they are from as the immunization strategy and risk-stratification relies on this data. Laboratory confirmation of cases based on collection and testing of cerebral spinal fluid (CSF) as well as blood sera will become increasingly important in areas where vaccination is implemented. If a case of encephalitis happens around the time of vaccination, testing CSF can determine if it was actually due to naturally acquired infection. In areas without vaccination, attention to new or emerging JE virus transmission with outbreak response will be essential. Depending on the scenario adopted for immunization, attention will need to be paid to areas where routine immunization is started without covering the total at-risk population. These sites will be likely areas for outbreaks to occur and will require close monitoring. Unfortunately by the time an outbreak is detected, viral amplification in Nature and transmission to humans would be

5 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

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well established in the community. At that time, immediate outbreak response may have little or no effect to to limit or stop transmission. JE has an incubation period of up to 2 weeks and antibody levels take 7-10 days after onset of illness to be reliably detected through the IgM ELISA. This results in about 3 weeks of gap from the time of exposure to detect an outbreak with lab confirmation. Outbreak response with immunization is not helpful with inactivated vaccine as it takes 2 doses and one month (total of 5 weeks) to have a protective immunity. The live vaccine has been used just prior (1 week) to an outbreak 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 established

Case management In Andhra Pradesh the setting up Encephalitis Treatment Centers (ETCs) in endemic districts 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 most endemic districts of the state with ‘manpower-medicine–equipment’ to provide clinical management of acute encephalitis syndrome (AES). The centers are also equipped with adequate referral support to higher centers of treatment. Enhanced care and treatment facilities are supported by intensified surveillance7 and diagnostics or AES in these districts. To improve patient outcome, similar training and site identification in endemic districts 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, 1998 and 2002 have emphasized that “human vaccination is the only effective long-term control measure against JE. All at-risk residents should receive a safe and efficacious vaccine 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 is considered 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 vaccine

The 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 technical support from VOXIVA established a real time web& telephone based reporting of AES cases from identified Public and Private facilities (5+5) in Kurnool in 2005. The system is currently under evaluation.

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Chapter III Japanese Encephalitis Vaccines

We quote below the most recent World health Organization (WHO) Position Paper on JE vaccines. WHO Position Paper.

25 AUGUST 2006, No. 34/35, 2006, 81, 325–340, http://www.who.int/wer, World Health Organization, Geneva

In accordance with its mandate to provide guidance to Member States on health policy matters, WHO is issuing a series of regularly updated position papers on vaccines and vaccine combinations against diseases that have an international public health impact. These papers, which are concerned primarily with the use of vaccines in large-scale immunization programmes, summarize essential background information on the respective diseases and vaccines, and conclude with the current WHO position concerning their use in the global context. The papers have been reviewed by a number of experts within and outside WHO and since April 2006 they are reviewed and endorsed 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 and immunization programme managers. However, they may also be of interest to international funding agencies, the vaccine manufacturing industry, the medical community and the scientific media. Summary and conclusions Japanese encephalitis (JE) is the most important form of viral encephalitis in Asia. It is estimated 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 15 000 cases of long-term, neuro-psychiatric sequelae. In recent decades, outbreaks of JE have occurred in several previously non-endemic areas. Infections are transmitted through mosquitoes that acquire the virus from viraemic animals, usually domestic pigs or water birds. Only about 1 in 250–500 infected individual smanifest clinical disease. There is no specific antiviral treatment for JE. Although the use of pesticides and improvements in agricultural practices may have contributed to the reduction of disease incidence in some countries, vaccination is the single most important control measure. Currently, the three types of JE vaccines in large-scale use are (i) the mouse brain-derived, purified and inactivated vaccine, which is based on either the Nakayama or Beijing strains of the JE virus and produced in several Asian countries; (ii) the cell culture-derived, inactivated JE vaccine based on the Beijing P-3 strain, and (iii) the cell culture-derived, live attenuated vaccine based on the SA 14-14-2 strain of the JE virus. Drawbacks of the mouse-brain vaccine are the limited duration of the induced protection, the need for multiple doses, and, in most countries, the relatively high price per dose. The cell culture-derived vaccines are manufactured and widely used in China, where the inactivated vaccine is gradually being replaced by the live attenuated vaccine. Several other promising JE vaccine candidates are in advanced stages of development. The need for increased regional and national awareness of JE and for international support to control the disease is urgent. JE vaccination should be extended to all areas where JE is a demonstrated public health problem. The most effective immunization strategy 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

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the routine immunization programme. This approach has a greater public health impact than either strategy separately. Both the mouse-brain derived and the cell culture-based vaccines are considered efficacious and to have an acceptable safety profile for use in children. However, with the mouse-brain derived vaccine, rare cases of potentially fatal acute disseminated encephalomyelitis and hypersensitivity reactions have been reported among vaccinated children in endemic regions and in travelers from non endemic locations. Because of the rarity 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 be deferred. The mouse-brain derived, inactivated vaccine has been used successfully to reduce the incidence of JE in a number of countries and is likely to be used nationally and internationally for some more years. The cell culture-based, live attenuated vaccine appears 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 immuno deficient people, as well as on the impact of co-administrating this vaccine with other vaccines. 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 local epidemiological circumstances and recommended schedules of other childhood vaccines. When immunizing children 1–3 years of age, the mouse brain-derived vaccine provides adequate protection throughout childhood following 2 primary doses 4 weeks apart and boosters after 1 year and subsequently at 3-yearly intervals until the age of 10–15 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 of about 1 year. The importance of achieving long-term protection is underlined by the observation that in some areas an increasing proportion of the JE cases occur in individuals older than 10 years of age. There is a need for safe and effective JE vaccines of assured supply. All manufacturers of JE vaccines should comply with the international standards for Good Manufacturing Practices and meet the WHO requirements for production and quality control. Whether locally produced or purchased from outside the country, the safety and immunogenicity of the vaccine must be assessed by independent national control authorities before it may be approved for use. Improved methods of JE surveillance including standardized, JE virus-specific laboratory tests are critical for characterizing the epidemiology, measuring the burden of disease, identifying high-risk populations and documenting the impact of control measures. The recommended standards for JE surveillance are discussed in a separate WHO document.2

Background Japanese encephalitis (JE) is a vector-borne, viral zoonosis that may also affect humans. JE occurs in practically all Asian countries, whether temperate, subtropical, or tropical, and has episodically intruded upon areas without enzootic transmission such as the Torres Strait Islands off the Australian Mainland. Nearly 3 billion people live in JE-endemic regions, where more than 70 million children are born each year. However, the annual incidence of clinical disease differs

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considerably from one country to the other as well as within affected countries, ranging from <10 to >100 per 100 000 population. The disease periodically becomes hyper endemic in areas such as northern India, parts of central and southern India, southern Nepal, northern Viet Nam as well as in areas of South-East Asia where vaccination programmes have not yet been instituted, e.g. in Cambodia. Anthropophilic culicine mosquitoes transfer the virus to humans from animal amplifying hosts, principally domestic pigs and wading birds. Culex tritaeniorhyncus, the most important vector species, breeds in water pools and flooded rice fields. Although the majority 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, and lasts until September or October. In tropical and subtropical areas, transmission exhibits less seasonal variation, or intensifies with the rainy season. Where irrigation permits mosquito 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 been introduced recently, serological surveys show that most people living in JE-endemic areas are infected before the age of 15 years. Only 1 in 250–500 JE viral infections are symptomatic. In hyper-endemic areas, half the number of JE cases occurs before the age of 4 years, and almost all before 10 years of age. Some endemic regions where childhood JE vaccination has been widely implemented have experienced a shift in the age distribution of cases towards an increasing proportion of cases occurring in older children and adults. In countries such as Japan and Korea, and in some regions of China, the incidence of JE has decreased during severaldecades, primarily as a result of extensive use of JE vaccines. Improved socioeconomic conditions, changed life styles and control measures such as centralized pig production and the use of insecticides may also have contributed to this development. Permethrin-impregnated mosquito nets have been shown to provide some protection against JE in one study. However, mosquito nets and other adjunctive interventions should not divert efforts from childhood JE vaccination. Whereas JE is believed to be grossly underreported among residents of endemic regions, the disease 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 by sudden onset of fever, chills, myalgias,mental confusion and sometimes nuchal rigidity. In children, gastrointestinal pain and vomiting may be the dominant initial symptoms and convulsions are very common. JE may present as a mild disease, leading to an uneventful recovery, or may rapidly progress to severe encephalitis with mental disturbances, general or focal neurological abnormalities and coma. Out of the approximately 50 000 cases of JE that are estimated to occur each year, about 10 000 end fatally, and about 15 000 of the survivors are left with neurological and/or psychiatric sequelae, requiring rehabilitation and continued care. Reports of JE disease in pregnant women are limited, as most infections occur in childhood, but studies from Uttar Pradesh (India), indicate a high risk of JE- associated abortion during the first two trimesters. The potential impact of concurrent infections, in particular HIV, on the outcome of JE virus infection is not yet established.

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The pathogen Japanese encephalitis virus belongs to the mostly vectorborne Flaviviridae, which are single-stranded RNA viruses. JE virus is antigenically related to several other flaviviruses that are prevalent in Asia, including dengue virus and West Nile virus. The envelope glycoprotein of the JE virus contains specific as well as cross-reactive, neutralizing epitopes. The major genotypes of this virus have different geographical distribution, but all belong to the same serotype and are similar in terms of virulence and host preference.Following an infectious mosquito bite, the initial viral replication occurs in local and regional lymph nodes. Viral invasion of the central nervous system occurs probably via the blood. Confirmation of a suspected case of JE requires laboratory diagnosis. The etiological diagnosis of JE is mainly based on serology using IgM-capture ELISA which detects specific IgM in the cerebrospinal fluid or in the blood of almost all patients within 7 days of onset of disease. Other methods include conventional antibody assays on paired sera for 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 culture from blood or CSF, but may be found in encephalitic brains at autopsy. JE-viral RNA is rarely 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 neutralizing antibodies $ 1:10 has been accepted as evidence of protection. A role for cell-mediated immune mechanisms in protection against JE virus has been demonstrated in experimental studies on mice. Vaccines against Japanese encephalitis Currently, 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 vaccine Historically, the mouse-brain derived, inactivated JE vaccine has been the most widely available JE vaccine on the international market. In the Republic of Korea, Thailand, and in areas of Malaysia, Sri Lanka, and Viet Nam, mouse brain-derived JE vaccine has been incorporated into the routine immunization programme. Liquid and lyophilized vaccines are both available for use. Current formulations of this vaccine are standardized in terms of immunogenicity and following extensive purification, its content of myelin basic protein has been reduced to minute amounts (<2 ng per ml). WHO technical specifications have been established for vaccine production3 Lyophilized mouse brain-derived vaccine is stable at 4 °C for at least 1 year. Although the Nakayama strain protects against JE virus strains from different Asian regions, other JE virus strains, such as the Beijing-1 strain, have induced stronger and broader neutralizing antibody responses in experimental, preclinical studies. For this reason, and because of the higher antigen yield in the mouse brain following inoculation of the Beijing strain, the Nakayama strain has been replaced in several mouse brain-

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derived JE vaccines. No evidence has been found of significant differences between these 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 <3 years. In several Asian trials, primary immunization based on 2 doses given at an interval of 1–2 weeks has induced protective concentrations of neutralizing antibodies in 94–100% of children aged >1 year. Although experience from Thailand shows that JE vaccination of children aged 6–12 months may be highly efficacious as well, in most epidemiological 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 with passively acquired maternal antibodies during the first months of life, vaccination is not recommended for children before the age of 6 months. In immunogenicity studies in the USA, seroconversion occurred only in approximately 80% of adult vaccines following an equivalent 2-dose schedule. In contrast, in US soldiers, a schedule based on vaccination on days 0, 7 and 30 resulted in 100% seroconversion. Following a booster injection approximately 1 year after the primary 2 doses, protective antibody levels have been achieved in practically all children and adults, regardless of geographical region. In people whose immunity is unlikely to be boosted by natural infection, repeated boosters are required for sustained immunity. Since the optimal number and timing of booster doses depend on the frequency of natural boosting with JE virus and possibly with related flaviviruses, the schedule for routine JE immunization has been difficult to standardize. Many Asian countries have adopted a schedule of 2 primary doses preferably 4 weeks apart, followed by a booster after 1 year. In some countries, subsequent boosters are recommended, usually at about 3-year intervals up to the age of 10–15 years. Australian studies following the outbreak of JE in the Torres Strait demonstrated that in the majority of children the level of neutralizing antibody declines to non-protective concentrations within 6–12 months following primary immunization. About 3 years after the primary series of 3 doses, or the last booster, only 37% of adults and 24% of children had 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 is required, boosters should be given after 1 year and then every 3 years. Current experience, primarily from Taiwan (China) and Thailand, does not suggest reduced 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 not been systematically studied. In general, the mouse brain-derived JE vaccine has been considered safe, although local reactions such as tenderness, redness and swelling occur in about 20% of vaccinated subjects. A similar percentage of vaccines may experience mild systemic symptoms, including headache, myalgia, gastrointestinal symptoms and fever. Acute disseminated encephalomyelitis (ADEM) temporally coinciding with JE immunization using the mouse brain-derived vaccine has been reported at frequencies corresponding

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to 1 case per 50 000–1 000 000 doses administered, but no definitive studies are available. Based on observations of a case of ADEM temporarily associated with JE Vaccination, the recommendation for routine childhood JE vaccination has been withdrawn in Japan. However, the Global Advisory Committee on Vaccine Safety4 concluded recently that there was no definite evidence of an increased risk of ADEM temporally associated with JE vaccination and that there was no good reason to change current 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 vaccine recipients from non-endemic areas. The reported rates of such reactions in prospective and retrospective studies are usually in the range of 18–64 per 10 000 vaccinated subjects. A complicating factor is that such reactions may occur as late as 12–72 hours following immunization. Sensitization to gelatine, a vaccine stabilizer, has been suspected in some cases in Japan, but the underlying cause remains uncertain. The only contraindication to the use of this vaccine is a history of hypersensitivity reactions to a previous dose. However, pregnant women should be vaccinated only when at high risk of exposure to the infection. Mouse brain-derived vaccine has been given safely in various states of immunodeficiency, including HIV infection. Cell culture-derived, inactivated vaccine Manufactured and available only in China, this vaccine is based upon the Beijing P-3 strain of JE virus, which provides broad immunity against heterologous JE viruses, and high viral yields when propagated in primary hamster kidney cells. A more recent version of the vaccine produced on Vero cells is licensed in China. Primary immunization of infants with this formalin-inactivated vaccine results in about 85% protection, but immunity wanes relatively rapidly. The vaccine has been used mainly in annual Chinese immunization campaigns before onset of the transmission season. Transient local reactions are reported in 4%, mild systemic reactions in <1%, and hypersensitivity in 1:15 000 of the vaccinated subjects. No case of acute vaccine-associated encephalitis has been reported. The vaccine is inexpensive, and previously, 75 million doses were distributed each year for internal Chinese use. This cell culturederived, inactivated vaccine is gradually being replaced by the cell culture-derived, live attenuated vaccine. Cell culture-derived, live attenuated vaccine This vaccine is based on the genetically stable, neuroattenuated SA 14-14-2 strain of the JE virus, which elicits broad immunity against heterologous JE viruses. Reversion to neurovirulence is considered highly unlikely. WHO technical specifications have been established for the vaccine production.5 As the vaccine is produced on primary cells, the manufacturing process includes detailed screening for endogenous and adventitious viruses. The live attenuated vaccine was licensed in China in 1989. Since then, more than 300 million doses have been produced and more than 200 million children have been vaccinated. Currently, more than 50 million doses of this vaccine are produced annually. Extensive use of this and other vaccines has significantly contributed to reducing 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 consistently shown 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 that even 1 dose of this vaccine can induce significant long-term protection (11 years in

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China). Carefully planned studies are required to establish firm recommendations on the optimal immunization schedule. In a prospective, randomized study involving more than 13 000 children actively monitored for 30 days, no cases of encephalitis or meningitis were observed, and no difference in hospitalization or prolonged fever was found between those who had received 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%, whereas redness and swelling at the site of injection occurred in <1%. Neither hypersensitivity reactions nor acute encephalitis have been associated with this vaccine. However, for immunization of pregnant women or immunodeficient individuals, the live attenuated vaccine should be replaced by one of the inactivated JE vaccines until further evidence has been generated. JE vaccines in advanced stages of development A promising genetic approach is the construction of a chimeric live attenuated vaccine comprising neutralizing antigen-coding sequences of the SA 14-14-2 strain of the JE virus inserted into the genome of the 17 D yellow fever vaccine strain. The resulting recombinant virus is cultivated on Vero cells. So far, the prototype of this vaccine has demonstrated 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 an inactivated JE vaccine based on the Beijing P-1 strain. Furthermore, the SA 14-14-2 viral strain has been adapted to Vero cells and the resulting experimental inactivated vaccine candidate has shown promising results in clinical trials. General WHO position on vaccines Vaccines for large-scale public health interventions should meet the current WHO quality requirements;6 be safe and have a significant impact against the actual disease in all target populations; if intended for infants or young children, be easily adapted to the schedules and timing of national childhood immunization programmes; not interfere significantly with the immune response to other vaccines given simultaneously; be formulated to meet common technical limitations, e.g. in terms of refrigeration and storage capacity; and be appropriately priced for different markets. WHO position on JE vaccines The need for increased regional and national awareness of JE and for international support to control this disease is urgent. With increasing availability of efficacious, safe and affordable vaccines, JE immunization should be integrated into the EPI programmes in all areas where JE constitutes a public health problem. The most effective immunization strategy in JE-endemic settings is one time catch-up campaigns including child health weeks or multi-antigen campaigns in the locally-defined primary target population, followed by incorporation of the JE vaccine into the routine immunization programme. This approach has a greater public health impact than either strategy separately. The three types of JE vaccines that are currently in large scale use are considered efficacious and acceptably safe for use in children. However, following immunization with the mouse brain-derived vaccine, rare cases of potentially fatal ADEM and hypersensitivity reactions have been reported among children in endemic regions and in travelers from non-endemic locations. An increased awareness of these specific adverse events is recommended, for example when assessing the actual risk of JE for the individual traveler. However, because of the rarity of these adverse events, and the greater benefit to risk ratio of routine vaccination, the introduction of immunization against JE in public health programmes should not be deferred.

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The now widely available cell culture-derived, live attenuated vaccine based on the SA 14-14-2 strain of JE virus and possibly the novel cell culture-derived, inactivated vaccines may offer suitable replacements for the mouse brain derived vaccine. The live attenuated vaccine induces protection for several years after 1 or 2 doses, whereas durable protection by the mouse brain-derived vaccine may require 2–3 initial doses followed by boosters at intervals of approximately 3 years. As the price per dose of the mouse brain-derived vaccine in most countries is higher than that of the live attenuated vaccine, the need for repeated doses renders the former vaccine unaffordable in many JE-endemic countries. Optimal national vaccination strategies depend on reliable information concerning the duration of protection and, additionally, whether repeated exposure to natural infection is required for long-term protection. Similarly, further information is needed on possible impact of cross-reacting flavivirus antibodies (e.g. dengue virus antibodies) on the outcome of primary JE immunization. All the currently used vaccines appear to protect equally well against infection by JE virus of different genotypes. For epidemiological, programmatic and economic reasons, JE immunization schedules differ widely from one country to the other. In general, using the mouse brain derived vaccine, adequate childhood protection is achieved following immunization of children as of 1 year of age with 2 primary doses 4 weeks apart followed by boosters after 1 year and subsequently at 3-yearly intervals up to the age of 10–15 years. Using the cell culture-based, live attenuated vaccine, equally good childhood protection is provided by a single dose of vaccine followed by a booster given at an interval of about 1 year. More information is expected to become available on possible interference between JE vaccines and simultaneously administered vaccines, as well as on the duration of protection. The principal Japanese manufacturer of mouse brain-derived JE vaccine has recently discontinued its production, and the quantity of this vaccine produced by other manufacturers is limited. Although ideally, the mouse brain-derived vaccine should be gradually replaced by new generation JE vaccines, short supply of JE vaccines in general will probably require continued production also of the mouse brain-derived vaccine for several more years. The rare, but potentially dangerous, adverse events associated with this vaccine make strict attention to current international quality requirements crucial for its continued production. Whether locally produced or purchased from outside the country, the safety and immunogenicity of the vaccine must be assessed by independent national control authorities before it may be approved for use. One of the manufacturers of the live attenuated vaccine is currently expanding its production capacity. In addition, new vaccines based on cell culture methods or modern recombinant technologies are now being introduced into immunization programmes or are in advanced stages of development. JE surveillance is critical for characterizing the epidemiology, measuring the burden of disease, identifying high-risk areas and areas of new disease activity, as well as for documenting the impact of control measures. Realizing the need to harmonize surveillance efforts in different countries, WHO has developed surveillance standards that also include specific recommendations on JE surveillance.

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Chapter IV The live attenuated JE virus SA-14-14-2

This chapter examines available information on the attenuated live virus vaccine against JE. 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 primary hamster kidney cells at National Institute for Control of Pharmaceutical and Biological Products (NICPPP) I Beijing in early 1970’s. This strain was shown to be safe and immunogenic in mice, pigs, horses and humans. Expanded field trials in Southern China involving more than 200,000 children confirmed the strain safety and yielded efficacious of 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 vaccine produced on primary hamster kidney cells and is being marketed in China since 1990’s also approved in Korea, Srilanka & Nepal etc. The said vaccine is allowed to import in the country after ensuring its safety and efficacy and other technical details as per norms and examined by panel of experts under DG ICMR, New Delhi. The vaccine is NOT recombinant derived vaccine, therefore GEAC was not consulted and moreover JE SA 114-2 strain is attenuated, which is not hazardous.” The following section is adapted from the brochure on the vaccine, obtained from the manufacturer, namely, the Chengdu Institute in China. [Constituents and characters] Japanese Encephalitis live vaccine is a preparation of live attenuated JE virus (strain SA 14-14-2) grown on the monolayer of hamster kidney cell cultures. After cultivation and harvest an appropriate stabilizer is added in the virus suspension, which is then lyophilized. The product looks like a light yellow crisp cake. After reconstitution, it shall turn into a clear, orange-red liquid. [Eligible’s] Healthy children above 8 months of age and those including children and adults who intend to enter the endemic area from non endemic area. [Function and uses] The product can induce immunity against JE virus in recipients following immunization. It is used to prevent Japanese encephalitis. [Specifications] 2.5ml of reconstituted vaccine per container 0.5ml per single human dose containing not less 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.

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[Adverse reaction] Transient fever any occur I few recipients, which normally does not last longer than 2 days and could be relieved spontaneously. Occasionally, sporadic skin rashes may appear 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, CHINA Address: Baojiang Bridge, Chengdu, Sichuan, China Zip code:610023 Telephone:86-28-84418968 Fax:86-28-84419941 Homepage:http//www.ronsen.com

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Chapter V

The licensing and procurement of the vaccine

The 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 and procurement through the established channels of the National Regulatory Agency (NRA). The matter was presented to the Directorate General of Health Services, and in particular the Drugs Controller General of India (DCGI). A request was made to the NRA for registering the product in India. The question was referred to the Indian Council of 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 and representatives 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.

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• 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 Maharajganj Deoria Kheri Sidhartnagar

Uttar Pradesh (15th May 06)

Saint Kabirnagar West Bengal (18th June 06) Bardhaman

Dibrugarh Assam (2nd July 06) Sibsagar Karnataka (2nd July 06) Bellary Vaccine Supply Protocol:

NDL/CDL for QC (Parallel) testing of

samples)

National Vaccine dose in Million

12- Apr 12-May 5.2 19- Apr 19-May 2.5 09-May 09-June 4 30-May 30-June 1.8

Shipment 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 1350 Vaccine requirement: State Vaccine Requirement

(Doses) Vaccine Requirement (Doses) in Million

Uttar Pradesh 6140616 + 2225916 6.14 + 2.3 West Bengal 2957133 2.95 Assam 955663 0.95 Karnataka 865488 0.86

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Chapter VI The vaccine use in the field

In this chapter a brief account of the implementation of the programme is given. This massive programme was implemented after much ground preparations, and a coalition of partnership consisting of the Government of India (Immunization Division), State Governments, UNICEF, WHO and Program for Appropriate Technology in Health (PATH). PATH had been assisting Andhra Pradesh for JE control activities over several years and was helpful in conceptualizing the present programme of JE vaccination in the 4 States. The monitoring of adverse events following immunization was a built-in component of implementation. At the end of the chapter the numbers of children vaccinated by geographic area and the numbers of reported AEFI are given in summary tables. 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 village

Key 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 AEFI

Units

• Planning : PHC • Implementation : Sub center • Vaccination site : Village

General 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

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• 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

population Vaccinating 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

area Role 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 center Role 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

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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 injection

Cold 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 packs

Team 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 medicines

Transportation 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 site

Supervision 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

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Recording and reporting o All formats to be used as mentioned in operational guideline.

Coverage data

Target Children (1-15 years)

No. of Children vaccinated

% Beneficiaries vaccinated

Koshi Nagar 1095877 1085055 99.01

Gorakhpur 1390307 1349047 97.03

Maharajganj 776500 806996 103.93

Deoria 1074219 1072683 99.86

Lakhimpur-Kheri 1183481 1218364 102.95

Sant Kabir Nagar 542062 511417 94.35

Siddharth Nagar 775934 792944 94.35

UTTAR PRADESH 6838380 6836506 99.97

Burdwan 2190690 1229404 56.12

WEST BENGAL 2190690 1229404 56.12

Dibrugarh 409611 370653 90.49

Sibsagar 372356 276487 74.25

ASSAM 781967 647140 82.76

Barelli 720517 595648 82.67

KARNATAKA 720517 595648 82.67

INDIA 10531554 9308698 88.39

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Report of Adverse Events following Immunization (AEFI) As a part of the monitoring of routine immunization program, any untoward events during the JE vaccination campaign was also monitored so as to fully investigate any adverse events that may have had occurred , even if insignificant or minor. The time interval of monitoring was 2 weeks from the day of injection.

Children vaccinated

AEFI cases

reported

Completely recovered

without hospitalization

Hospitalized Death

Koshi nagar 1085055 18 11 7 4

Gorakhpur 1349047 85 71 14 2

Maharajganj 806996 50 42 8 1

Deoria 1072683 55 54 1 0

Lakhimpur-Kheri 1218364 10 10 0 0

Sant Kabir Nagar 511417 4 4 0 0

SiddhartNagar 792944 0 0 0 0

UTTAR PRADESH 6836506 222 192 30 7

Burdwan 1229404 24 16 7 6

WEST BENGAL 1229404 24 16 7 6

Dibrugarh 370653 49 38 11 3

Sibsagar 276487 66 53 13 4

ASSAM 647140 115 91 24 7

Bellary 595648 143 140 2 2

KARNATAKA 595648 143 140 2 2

INDIA 9308698 504 439 63 22

31

Chapter VII

AEFI Reports: Magnitude and Spectrum.

Vaccination campaign with the live attenuated JE vaccine was conducted in 11 districts of 4 states during May to July 2006. The campaign began on 15 May 2006 in the State of Uttar Pradesh in the districts of Gorakhpur, Maharajganj, Kushinagar, Deoria and Kheri. The campaign in the UP districts of Sant Kabirnagar and Siddharthnagar began on 20 May 2006. The campaign in Burdwan, West Bengal began on 18 June 2006 and the campaign in Dibrugarh and Sibsagar districts in Assam as well as in Bellary district in Karnataka began on 2 July 2006. Cases of Adverse Events Following Immunization (AEFI) were reported in nearly all districts except the district of Siddharthnagar in UP. Very few AEFI were reported in the districts of Sant Kabirnagar and Kheri in UP. In various pre-campaign preparatory meetings the importance of AEFI detection and reporting was emphasized. Also in the advisories issued during the campaign and again after the campaigns – all concerned officers in States and districts were requested to ensure that reports regarding AEFI cases were collected and forwarded to the Immunisation Division under the Ministry of Health and Family Welfare, New Delhi. During the campaign there was a team from the implementation partnership – GoI, State Governments, UNICEF, WHO and the Program for Appropriate Technology for Health (PATH) that visited the programme sites and helped both the implementation and the monitoring of AEFI. After the completion of the campaign, another team was sent by the GoI to collect information on AEFI and it visited institutions where children with reported AEFI were hospitalized. Thus the data set on AEFI was the result of all these efforts put together. The reports thus received were analyzed in the Division. The combined line list gives a total report of 533 AEFI cases, including 22 deaths. The details are given in table 1 below.

Table 1 : Line List and Source S No. AEFI list No. 1. Non Serious 4382. Serious Recovered 433.

UIP Section Death 22

4. GOI team in UP Additional names from Gorakhpur Line List 30Total AEFI 533

AEFI cases and deaths in 11 districts and 4 states following JE immunization

AEFI requiring no hospital care,

446, 88%

AEFI deaths, 22, 4%

AEFI requiring hospitalization but improved,

43, 8%

32

The campaign in the respective districts began as in table 2 and the approximate duration of the campaign was as given. The campaign continued from 1 to 2 weeks. The period 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 12Maharajganj 17-May 29-May 13Kushinagar 15-May 25-May 11Kheri 15-May 26-May 12Sant Kabirnagar 23-May 29-May 7Siddharthnagar 20 May NA NADeoria 15-May 29-May 15Gorakhpur 15-May 27-May 13Bellary 10-Jul 15-Jul 6Dibrugarh 2-Jul 15-Jul 14Sibsagar 2-Jul 14-Jul 13

The GoI (Immunization Division) prescribed a format for reporting of AEFI during and for 14 days after this campaign. The reports were generally in this format at 2 levels – the First Information Report (FIR) by Health Workers or Peripheral Health Personnel and the Preliminary Information Report (PIR) by the Medical Officer investigating an FIR. The Division had access to the PIRs and also the photocopies of case records of children who were hospitalized for AEFI. However, among all reports, there was no clinical information recorded for 47 children. They have been excluded from further consideration in this report. That leaves 486 cases of AEFI, available for analysis. The broad clinical features of these cases are summarized in Table 3. (The table includes multiple entries, in case of more than one clinical feature, for which reason the totals may not tally.)

Table 3 : Clinical Features of AEFI Cases

District Fever immediate

Fever < 3 d

Fever > 3 d Vomiting Convulsion

Other Neuro Sign ARI Rash

Burdwan 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 0Siddharth nagar Deoria 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

33

These 486 cases were reclassified for their cumulative clinical features to make the

features statistically mutually exclusive events and the result is given in Table 4. These adverse reactions were reported as any illness occurring either on the day of vaccination or within a period of 14 days. The gap between the day of vaccination and the day of reaction is shown in table 5 below. 68.5 % of AEFI were reported on the day of vaccination, 10.0 % reported next day, 11.7% on 2nd day post vaccination, 2.6% on 3rd day post vaccination and all AEFI reporting 4 or more days after vaccination constitute 6.9%.

Table 5 : Gap between JE vaccination and AEFI reporting in days

District 0 da

y af

ter

vacc

inat

ion

1 da

y af

ter

vacc

inat

ion

2 da

ys a

fter

vacc

inat

ion

3 da

ys a

fter

vacc

inat

ion

4 da

ys a

fter

vacc

inat

ion

Tota

l

Burdwan 20 2 0 0 1 23Maharajganj 30 9 5 1 4 49Kushinagar 9 3 1 1 4 18Kheri 9 0 0 0 1 10Sant Kabir 4 0 0 0 0 4Siddharth nagar 0 0 0 0 0 0Deoria 38 8 4 1 2 53Gorakhpur 54 14 9 5 3 85Bellary 135 1 2 0 2 140Dibrugarh 17 7 2 3 10 39Sibsagar 17 5 34 2 7 65Total 333 49 57 13 34 486

Table 4 : Classification of syndromes of AEFI

District Con

vuls

ion

+/-

othe

r neu

ro

sign

s

Con

vuls

ion

+/-

othe

r neu

ro

sign

s no

Fev

er

Feve

r no

conv

ulsi

on/

neur

olog

ical

si

gn

Ras

h &

Fev

er

Ras

h no

feve

r

Onl

y Vo

miti

ng

only

AR

I

Mis

cella

neou

s

AEF

I

Tota

l

Burdwan 3 0 12 1 2 4 1 0 23Maharajganj 2 5 22 1 2 3 0 14 49Kushinagar 6 1 6 0 0 0 0 5 18Kheri 0 0 1 1 1 1 0 6 10Sant Kabir nagar 0 0 2 0 0 2 0 0 4Siddharth nagar 0 0 0 0 0 0 0 0 0Deoria 1 0 33 1 6 5 1 6 53Gorakhpur 11 2 38 0 10 9 0 15 85Bellary 3 0 53 0 26 18 1 39 140Dibrugarh 9 0 9 1 1 11 0 8 39Sibsagar 5 2 55 0 0 0 0 3 65Total 40 10 231 5 48 53 3 96 486

34

Gap between vaccination and reporting AEFI

333

49

57

13

34

0 50 100 150 200 250 300 350

0 day after vaccination

2 days after

4 or more days after

As is given in table 4 the line list recorded cases that do not have any feature suggestive of AEFI. For analyzing categories of AEFI the cases were further screened and 96 such cases were removed from the list of 486 cases for which sufficient clinical features were not available for meaningful analysis. Some cases had entries in the remarks column. This information was used to update the clinical features field. Thus the available 390 cases with sufficient clinical information are classified in table 6.

Table 6 : Classification of AEFI into broad groups

District Loca

l re

actio

ns

(ras

h on

ly)

Mild

sy

stem

ic

reac

tions

(fe

ver+

/- R

ash

+/-A

RI/

vom

iting

) re

actio

ns/

Ac

Ence

phal

itis

(con

vuls

ion

+/-

Neu

rolo

gica

l Sig

ns +

/- Fe

ver)

Total

Burdwan 2 18 3 23Maharajganj 2 26 7 35Kushinagar 0 6 7 13Kheri 1 3 0 4Sant Kabir nagar 0 4 0 4Siddharth nagar 0 0 0 0Deoria 6 40 1 47Gorakhpur 10 47 13 70Bellary 26 72 3 101Dibrugarh 1 21 9 31Sibsagar 0 55 7 62Total 48 292 50 390

From the data given in Chapter VI, incidence of AEFI cases are calculated and placed in Table 7 below.

35

Table 7 : Type of AEFI by severity

Local reactions (rash only)

Mild systemic reactions (fever+/- Rash +/-ARI/ vomiting

Severe reactions/ Ac Encephalitis (convulsion +/- Neurological Signs +/- Fever)

Total

Number of cases 48

292

50

390

% of total cases 12.3

74.8 12.8 99.9

Number of Immunized 9308698

Incidence of Cases/ lakh

0.51 3.13 0.53 4.18

Thus the incidence of AEFI in the current campaign was 4.18/ 100,000 (one lakh), overall. Of this, 0.51/ lakh was incidence of local reactions. Systemic reaction incidence was 3.66/ lakh and incidence of serious reactions was 0.53/ lakh. The frequency of fatality was 0.23/ lakh.

Type of AEFI by severity

Mild systemic reactions , 292,

75%

Severe reactions, 50,

13%

Local reactions , 48, 12%

The age pattern of these AEFI cases is given in table 8 below.

Table 8: Age distribution of AEFI cases (n = 390)

Age (YRS) No. % 1 to 4 98 25.1 5 to 9 146 37.4 >9 142 36.4 Not available 4 1

36

Chapter VIII Studies in Progress on Vaccine Safety

While the AEFI monitoring has generated much data and information on the safety

aspect of the live JE vaccine, the planning of vaccination had included further focused

investigation on vaccine safety in an institutional setting. Two institutions were chosen,

one in west Bengal and another in Karnataka. These two institutional studies will also

measure antibody response in children given the vaccine. The Committee has not

explored the current progress of these studies but include the broad study plan for

completing the present scene on the safety issue and quote from a report on the

preliminary results from one study site. TITLE OF THE STUDY An Open Label, Multicenter, Post Marketing Study to Evaluate the Safety and

Immunogenicity of a Single Dose of Live Attenuated Japanese Encephalitis (JE) Vaccine

SA 14-14-2 in Children

OBJECTIVES Primary Objective - To evaluate the safety of a single dose of live attenuated Japanese encephalitis

vaccine SA 14-14-2 administered in children 1-15 years of age for 28 days.

- To evaluate serious adverse events of live attenuated Japanese encephalitis vaccine

SA 14-14-14-2 administered in children 1-15 years of age for a period of 12 months

post vaccination.

Secondary Objectives - To evaluate immunogenicity of a single dose of live attenuated Japanese

encephalitis vaccine SA 14-14-2 administered in children 1-15 years OUTCOMES Primary - Occurrence of any adverse reactions including serious adverse reactions within 30

minutes following the vaccination.

- Occurrence of “common, minor vaccine reactions” like pain, redness, swelling, fever,

nausea, vomiting and loss of appetite in the 4 week period following vaccination.

Occurrence of “rare serious vaccine reactions” in the 4 week period following

vaccination. Rare serious vaccine reactions are adverse events that could occur with

any vaccine. They include anaphylactoid reaction, anaphylaxis,

hypotonic/hyporesponsive episode (HHE) or shock collapse, seizures

- Occurrence of unsolicited or unlisted adverse events during the 4-week period post

vaccination.

37

- Serious adverse events during the 12-month period post vaccination

Secondary - GMTs (geometric mean titers) of neutralizing antibody to the SA14-14-2 and Indian

strains of JE virus and their 95% CI

- Seroconversion and seroprotection rates with their 95% CI at baseline, 28 days, 6

and 12 months overall, by age categories and by baseline nutritional status (weight

for age and weight for height/length).

STUDY SITES Burdwan Medical College, Burdwan, West Bengal

Vijayanagar Institute for Medical Sciences, Bellary, Karnataka

STUDY POPULATION Children 1 to 15 years of age whose parents consent to participate and children (>7

years) give assent to, will participate in the study i.e. 480 in each of the three age

categories. Safety Group Around 1200 children will be evaluated for safety; 400 each in the age categories 1-5

years, 6-10 years and 11-15 years. Adjusting for a drop out rate of about 20%, 1440

children will be enrolled in the study. Immunogenicity Group At least 300 children will be evaluated for immunogenicity. Adjusting for a drop out rate

of about 20%, in each stratum, 120 children in each age subgroup i.e. 1-5 years, 6-10

years and 11 to 15 years will be assessed for immunogenicity, 360 children will be

enrolled in this group for the study. PRODUCT DESCRIPTION Live attenuated JE virus strain SA 14-14-2 vaccine.

INCLUSION CRITERIA FOR SAFETY AND IMMUNOGENICITY GROUPS ON THE DAY OF ENROLLMENT • Subject aged 12 months or older and less than 15 years.

• Written informed consent/assent (if child >7 years old) is available from the subjects’

parents or guardians/child.

• Subject intends to reside at the current place for at least 12 months from the date of

vaccination.

• Free of obvious health problems as established by medical history and clinical

examination.

EXCLUSION CRITERIA

• Subject has received any live vaccines in the last 4 weeks.

38

• History of allergic disease or reactions likely to be exacerbated by any component of

the vaccine.

• History of documented HIV.

• Known or suspected impairment of immunologic function.

• History of serious chronic disease (e.g., cardiac, renal, neurologic, metabolic,

rheumatologic).

• Underlying medical condition such as inborn errors of metabolism, failure to thrive,

bronchopulmonary dysplasia, or any major congenital abnormalities requiring

surgery or chronic treatment.

• Acute disease at the time of enrollment. (defined as the presence of a moderate or

severe illness with or without fever. All vaccines can be administered to persons with

a minor illness such as diarrhea, mild upper respiratory infection with or without low-

grade febrile illness.)

• Axillary temperature at time of vaccination >37.5ºC (99.5°F)

• History of documented suspected encephalitis, encephalopathy, or meningitis

• History of Thrombocytopenic purpura.

• Received any JE vaccine since birth.

• History of hypotonic – hyporesponsiveness, after a preceding vaccination.

• History of seizures, including history of febrile seizures, or any other neurologic

disorder.

• Prior or anticipated receipt of immune globulin or other blood products, or injected or

oral corticosteroids or other immune modulator therapy except routine vaccines

within 6 weeks of administration of the study vaccines. Children on a tapering dose

schedule of oral steroids lasting <7 days may be included in the trial as long as they

have not received more than one course within the last 2 weeks prior to enrollment.

• Suspected or known hypersensitivity to any of the investigational or marketed

vaccine components.

• Enrolled in another clinical trial involving any therapy.

• Any condition that in the opinion of the investigator, would pose a health risk to the

participant, or interfere with the evaluation of the study objectives. ANALYSIS - Prevalence of vaccine reactions overall and in different age categories

- Prevalence of adverse events (including serious adverse events) overall and by age

categories

39

- Seroconversion and seroprotection rates 28 days, 6 and 12 months post vaccination

overall, by age categories and by baseline nutritional status (weight for age and

weight for height/length). - GMTs (geometric mean titers) of neutralizing antibody to the SA14-14-2 and Indian

strains and their 95% CI

STUDY DURATION Following vaccination the children included in the safety group will be followed up for 28

days (±2 days) for vaccine reactions and other adverse events. Subsequently, 3 monthly

visits (at 3, 6, 9 and 12 months post vaccination) will be made for ascertainment of

serious adverse events. Those in the immunogenicity group will additionally be sampled

prior to vaccination, at day 28 (+2days) and at 6 and 12 months post vaccination. PLANNED STUDY PERIOD Field Work June 2006 to August 2007

Analysis and report writing September 2007 to November 2007

Preliminary Report on vaccine safety and efficacy. (Anx-4) Preliminary Report

(For 28 Days Post Vaccination) Study Site: Bellary, Karnataka Prepared By: Society for Applied Studies, New Delhi

RESULTS Of the 887 children screened, 293 were in the age group 1-5 years, 256 in the age group

6-10 years and 256 in the age group 11-15 years. The reasons for exclusion of the

volunteers based on a priori criteria are listed in Figure 1. A total of 252, 235 and 230

were enrolled and vaccinated in the age groups 1-5 years, 6-10 years and 11-15 years

respectively.

Adverse Events No serious vaccine reactions were reported in the first 30 minutes post vaccination when

the children were observed in the vaccination centre (Table 1).

No serious adverse events were reported in the 28 day period post vaccination; all

adverse events reported were of mild or moderate grade in severity.

The children were followed up by home or school visits. The number of children not

available for follow up during week 1, 2, 3 and 4 post vaccination were 2, 8, 4 and 4

respectively.

40

Adverse events were reported for days 0-7 (week 1), 8-14 (week 2) and 15-21 (week 3)

and 22-28 (week 4) post vaccination (Table 2). The most commonly reported adverse

events were the common minor vaccine reactions i.e. fever, pain, redness or swelling at

vaccination site, nausea or vomiting and loss of appetite. In the first week post

vaccination, fever (49 children), pain at vaccination site (26 children) and vomiting (14

children) were reported. Fever was reported by 10 children each in weeks 2 and 3, and

by 5 children in week 4 post vaccination. A Chickungunya epidemic was also reported in

the state at the time of the trial. Other commonly reported adverse events during the first

week were cough (26 children), running nose (35 children), abdominal pain (10 children)

and headache (15 children). These symptoms reduced during the second week of follow

up and the occurrence of complaints during this period was cough (5 children), running

nose (4 children), abdominal pain (2 children) and headache (3 children).

Fever, nausea or vomiting, and rash are mentioned in the vaccine package insert as

expected adverse events. In the first week following vaccine administration, 49 (6.9%)

children reported fever, 5 (0.7%) children reported nausea, 14 (2.0%) children reported

vomiting and 4 children reported rash (Table 3).

In the second week post vaccination, the number reduced to 10 (1.5%) children with

fever, one with nausea and 2 with vomiting; no cases of rash were reported (Table 3).

The subject wise listing of adverse events for the first 4 weeks post vaccination are

provided in Table 4, 5, 6 and 7.

Concomitant medications During the first week post vaccination, 22 (15.8%) out of the 139 children with adverse

events received any medications. During weeks 2, 3 and 4 post vaccination, 6 out of 25,

11 out of 24 and 4 out of 14 children with adverse events received medications

respectively.

LIMITATIONS OF THE REPORT It may be noted that preparation of the report at this stage is not a part of the Project

Agreement signed with the sponsor. As a request was made to us, we have tried to

comply but since sufficient time was not available for cleaning and cross checking of

data we cannot exclude the possibility of any errors at this stage.

CONCLUSIONS Although no definitive conclusions can be made due to the lack of a control group from

the data available, the vaccine appears safe as:

41

- No rare serious vaccine occurred reactions within 30 minutes post vaccination

- No serious adverse event occurred during the 28 days post vaccination - Prevalence of common minor vaccine reactions and other adverse events was low

Day of Study Schedule of Events:Activity

0

1 to

7

daily

vi

sits

14 (+

2)

21 (+

2)

28 (+

2)

Mon

th 3

(+

7 d)

Mon

th 6

(+

7 d)

Mon

th 9

(+

7 d)

Mon

th

12 (+

14

d)

Informed consent/assent

Medical History

Physical exam including vital signs

Vaccination

Home visits

Record concomitant medications

Assess minor vaccine reactions

within

30 minutes

Assess rare serious vaccine reactions

within

30 minutes

Assess adverse events

within

30 minutes

Assess serious adverse events

within

30 minutes

Blood sample for those in immunogenicity group

42

Chapter IX

Committee’s Observations and Conclusions General It must be stated that the Committee had a very difficult task in identifying the nature of serious illnesses in the 65 children (64 hospitalized) and particularly the causes of death in the 22 among them (21 hospitalized). The deficiencies are both at the performance level of many of the doctors and also at the documentation level by them. In too many instances the illness of the child was not properly diagnosed or diagnosis recorded. Laboratory investigation was very frugal, insufficient in many. Case records were quite inadequate and in too many cases doctors did not write follow up notes or their reasons for the diagnosis or treatment.

Even when diagnosed correctly, the treatment did not conform to any protocol or uniform standard in several cases. It was very unfortunate that in some cases the doctors had already made a diagnosis of “JE vaccine illness” and further pursuit of the nature and cause of illness was abandoned. This illustrates an important methodological problem in determining “causality” through observational study without “control” observations. Once doctors were asked to be on the lookout for AEFI, the tendency was, for some of them, to be biased. This is well illustrated in some children in whom natural illnesses were mindlessly misclassified as “JE vaccine illness”.

Understandably neurological illnesses would deserve careful assessment for causality by live virus JE vaccination. The standard of diagnosis and documentation left much to be desired, adding to our difficulties. Clinicians seemed not to distinguish between an ‘encephalitic disease’ (without intracranial hypertension, but with CSF pleocytosis, and presumed to be infectious) and an ‘encephalopathy disease’ (often with intracranial hypertension, but without CSF pleocytosis, and presumed to be non-infectious). This distinction has serious implications in terms of case management. Strangely, the lack of discriminatory discussion by the doctors had crossed into the territory of treatment as well. Having diagnosed as encephalitis or encephalopathy, the administration of two antimicrobials by injection, the addition of injection of quinine even when malaria had been excluded, the injection of mannitol (to reduce brain oedema) even after noting that the CSF pressure was normal or not elevated, giving mannitol in cases diagnosed to have ‘encephalitis’ etc. are some of the obvious suggestive evidences of unclear thinking and treatment, more by ‘habit’ rather than by rationale. Once treatment was commenced, the daily reassessment was conspicuous by absence. Several of these issues are illustrated by specific case summaries given in Annexure No. abc. Approach to causality We approached the need to determine causality of adverse events following immunization in the following manner. Essentially we asked if the illnesses could have been causally associated with the vaccine, or merely temporally associated but coincidental. We re-examined diagnoses and clinically scrutinized available clinical records and misclassifications were corrected within the limitations of very poor quality case records. We also asked if the disease were common or uncommon. Could the diseases have occurred as coincidental events particularly since the number of children involved was truly enormous. We scrutinized the diagnostic categories for any specific patterns – especially since the number of children vaccinated was very large and if any AEFI was causally associated, we argued, that a pattern might emerge. No such pattern was clear but, but two clusters of illnesses stood out among all diagnoses. Both were brain diseases – the vaccine is an attenuated form of a brain-tropic virus. Therefore we had to weigh all available data and evidences, along with our knowledge of the

43

background of illnesses – particularly the diseases represented by the same two clusters. We weighed the evidence at four levels and asked:

• Did the evidence establish causal association? • Was the evidence inadequate to accept or reject causal association? • Did the evidence favour the rejection of causal association? • Did the evidence establish absence of causal association?

Observations on death cases following vaccination:

First we examine the 22 cases of death, 21 in the hospital and 1 on the way to

hospital. In children with encephalopathy, we believe that careful frequent monitoring, treatment for reducing brain oedema, correcting hypoglycaemia and nursing care to prevent aspiration etc. would probably have saved several lives.

The frequency of 22 deaths among 9.308 million vaccinated children aged 1-15 years work out as 0.236 / 100000 (0.00024%). Based on the population (Census 2001), annual growth rate, estimated number of children and age specific death rates we arrived at the probable frequency of death in 1-14 year age group in the general population in the districts in which JE vaccination campaign was conducted comes to 8.63 / 100000 (0.009%). The number of death in the two weeks after JE vaccination has not exceeded this background rate. Thus there seems to be no prima facie evidence that AEFI has contributed any excess mortality What were the diagnoses? We examined each case history and laboratory findings when available, and made our own diagnosis in each case. Needless to say that we concurred in some, but we also disagreed in many. The line-listing of the 22 cases is given in Appendix No 3.. In examining the clinical features of the 22 children, we were handicapped without a grasp of the quantitative prevalence of the “background noise” of illnesses prevalent at each location around the time when JE vaccination was conducted. There appeared to be two ‘clusters’ of ‘syndromes’ that were temporally associated with the JE vaccination. We asked if these illnesses could have been naturally occurring or ‘artificially’ induced by the vaccine as AEFI. For these diagnoses we ask if there was biological plausibility for causal association. We also examined if these cases could have alternate explanations for clustering. Other than the two ‘clusters’ there were 8 cases in which the diagnosis was accepted as ‘natural’ and they were classified according the fourth bullet: evidence established absence of causal association.

The clusters of illnesses were: One, an encephalopathy syndrome, with onset of symptoms within 72 hours of JE vaccination and death within 7 days of onset of illness. There were 9 such cases. They were as follows. Case No. Age(yr) State District 01 10 UP Maharajganj 04 6 UP Kushinagar 05 7 UP Kushinagar 06 3 UP Gorakhpur 07 6 UP Gorakhpur 08 9 WB Burdwan 14 7 KAR Bellary 15 4 KAR Bellary 21 6 Assam Sibsagar

44

The second was an encephalitis syndrome, with onset any time during the two weeks after JE vaccination. There were 5 such cases. Case No. Age(yr) State District 16 5 Assam Dibrugarh 18 7 Assam Dibrugarh 19 12 Assam Sibsagar 20 6 Assam Sibsagar 22 5 Assam Sibsagar The remaining cases could be classified as under. Encephalopathy of late onset. Case No 17. 8 yr Assam Dibrugarh Other central nervous system diseases. Intracranial suppuration and coning of brain Case No 02 6 yr UP Khushinagar Acute flaccid paralysis, quadruparesis (possible bulbar polio or Guillain-Barre) Case No 03 3yr UP Khushinagar Hepatic encephalopathy Case No 09 2 yr WB Burdwan Others (non-CNS) Acute gastroenteritis Case No 10 1 yr WB Burdwan Pneumonia Case No 11 5 yr WB Burdwan Case No 12 12 WB Burdwan Severe Asthma Case No 13 14 WB Burdwan Laboratory studies. Report on the testing of samples received from cases of Adverse Reactions following immunization with SA-14-14-2 JE vaccine (Anx-5) Samples of patients with Adverse reactions following SA-14-14-2 vaccine administration in Gorakhpur areas were received from NICD. 17 CSF samples and two sera sample from cases admitted at BRD Medical College and 5 sera samples from Uttar Pradesh Public Health team were received. One vial of CSF was empty and in one the quantity as very low.

45

As per the instructions received from Director General, ICMR following tests were carried out on these samples.

1. Detection of IgM antibodies against JE virus by IgM antibody capture ELISA.

2. RT PCR on CSF samples for detection of JE virus genome

3. Inoculation of CSF samples in BHK cells for detection of virus growth. 4. Real Time PCR for detection of JE virus genome in CSF samples.

1. It was observed that IgM anti JE virus antibodies were not detectable in 14

out of 16 CSF samples tested. Two CSF samples showed very low borderline reactivity with JE virus. In both cases onset of symptoms as per the data provided was 1 and 2 days post vaccination, hence these antibodies may not be related to vaccination.

2. RT-PCR using flavivirus specific primer pairs were carried out on all CSF samples. None of the samples showed presence of JE virus RNA. Further, nested PCR was also carried out for increased sensitivity and none of the samples showed presence of JE virus genomes. Both JE virus and SA-14-14-2 virus controls could be detected using these primer pairs.

3. All CSF samples were inoculated in BHK cells that are sensitive to both wild type JE and attenuated JE virus. All the cultures were observed for more than 6 days. No signs of any cytopathichic effect indicating virus growth were observed.

4. None of the samples showed any signal for genome of JE virus in the CSF samples by Real Time PCR.

The tests indicated that the samples received did not show presence of wile type

of vaccine JE virus. Causality assessment Except for the two clusters, all others such as late onset encephalopathy, AFP with brain function involvement, hepatic encephalopathy, gastroenteritis, pneumonia and asthma are considered to be causally unrelated to JE vaccination. Thus they belong to the category ‘the evidence established absence of causal association.’ The cluster of 5 encephalitis cases were geographically limited to Assam, and we understand that an outbreak of what aoppears to be JE had already started in several districts of Assam, particularly in Dibrugar and Sibsagar. Therefore we consider them natural JE, rather than caused by JE vaccine. The main reasoning is that these were confined to the known region with an outbreak of JE but not in other places. Moreover, they were in children 5 or above, whereas vaccine was given to children from 1 year. Natural JE has the same range of age, whereas if JE vaccine were to cause encephalitis we would have expected them more in younger children – or at least evenly distributed across all ages from 1 to 15. On the other hand we know that the vaccine virus is attenuated JE and the one adverse event we do not want to occur in vaccinated children is encephalitis. For these reasons and as a lead to investigate the possibility of encephalitis causation by JE vaccine, even if considered unlikely, we are classifying

46

them as most likely unrelated. We classify this cluster in the category ‘evidence favour the rejection of causal association’. The cluster of encephalopathy cases requires careful scrutiny. There are points in favour and against this illness as a reaction to JE vaccine. The points suggesting causative relationship are the timing, the uniformity of clinical picture and the fact that it occurred in UP, Karnataka, West Bengal and in Assam. The timing is the most important issue. The cluster had onset within 24 to 72 hours of JE vaccination. Only one such case occurred at a time point outside this narrow range – that was case No 17, with onset 8 days after vaccination. The disease is neurological, with brain involvement. The clinical picture has many common features – brain oedema, lack of CSF pleocytosis, rapid course of illness, death. On the other hand, the clinical picture is identical with annual outbreaks in many parts of Northern India. Such cases were first documented in 1954 and called Jamshedpur fever. Later it was called “Nagpur encephalitis” – but on investigation it was reclassified as acute encephalopathy, very similar to Reye syndrome. Such outbreaks have been documented in Haryana, UP, West Bengal and in Andhra Pradesh. So, this disease is geographically occurring and “peculiar” to this population. Unfortunately the cause of these outbreaks has not been fully investigated. There has been limited studies and claims that they are caused by silent measles virus infection (measles without rash) and by Chandipura virus. Most experts dismiss both theories. Thus, the pathology, pathogenesis, the risk factors and causative factors have not been worked, a situation we find very disturbing. Such outbreaks have not been reported in Bellary in Karnataka, but that does not mean that the possibility could be excluded. Outbreaks of Reye syndrome have been reported in Karnataka.

Could the vaccine have somehow “triggered” this encephalopathy, to which children are prone due to some unknown factors? Were there similar cases clustering over the same days/week as the JE vaccination? We do not have data to access to the necessary information to check if unvaccinated children had acute encephalopathy around this time; hence it is not possible to exclude the possibility, however much unlikely that may be, that the vaccine did not cause or trigger the cases. In summary, we consider the evidence insufficient to establish causal association. There was no case that we considered as having evidence that established causal association with the JE vaccination. Children who recovered after hospitalization There were 64 children hospitalized within 2 weeks of JE vaccination, among who 21 died. They were the subject of scrutiny in the subsections given above. The remaining 43 children were considered to be ill with symptoms/signs that warranted hospitalization. Therefore we consider them as serious AEFI events, without in any way attributing causality, but recognizing only temporal association. Considering the total number of children vaccinated (9.308 millions) the proportion that developed serious illnesses amount to 0.069 per hundred thousand. We do not have data to compare the natural frequency of hospitalisable illnesses in 1-15 year-age group of children. Once again the two clusters of illnesses – an acute encephalopathy syndrome and an acute encephalitis illness stand out prominently.

47

Encephalopathy syndrome, onset within 72 hours and recovery within a week. Case No. Age(yr) State District 4 2 Assam Dibrugarh 28 5 UP Kushinagar 29 6 UP Kushinagar 31 2 UP Gorakhpur 32 2 UP Gorakhpur 36 4 UP Gorakhpur Late onset acute encephalopathy syndrome 40 7 UP Gorakhpur 42 6 UP Gorakhpur Acute encephalitis Case No Age State District Time interval from Vaccination to onset 1 8 Assam Dibrugarh 9 days 2 12 Assam Dibrugarh 11 day 3 8 Assam Dibrugarh 8 days 5 9 Assam Dibrugarh 1 day 7 3 Assam Dibrugarh 11 days 9 7 Assam Sibsagar 8 days 10 9 Assam Sibsagar 3 days 11 5 Assam Sibsagar 2 days 20 8 UP Maharajganj 1 day Seizures without evidence of encephalitis or encephalopathy Case No Age State District Time interval from Vaccination to onset 19 7 Karnataka Bellary 5 days 25 10 UP Maharajganj 19 days 26 9 UP Maharajganj 17 days 43 1 UP Deoria 4 days Other CNS diseases Case No Age State District Time interval from Vaccination to onset Neurocysticercosis 8 2 Assam Dibrugarh 4 days Aseptic meningitis 38 3 UP Gorakhpur 5 days Bacterial meningitis 37 15 UP Gorakhpur 2 days 41 10 UP Gorakhpur 5 days Acute hemiplegia 38 8 UP Maharajganj 1 day

48

Other diseases Case No Age State District Time interval from Vaccination to onset Short fever (of less than 5 days duration) 12 6 Assam Sibsagar 0 day 13 9 Assam Sibsagar 0 day 14 7 Assam Sibsagar 1 day 15 4 Assam Sibsagar 14 days 16 15 Assam Sibsagar 2 days 22 8 UP Maharajganj 0 day 30 8 UP Gorakhpur 0 day 33 2 UP Gorakhpur 0 day 35 12 UP Gorakhpur 0 day Acute gastroenteritis 6 4 Assam Dibrugarh 4 days 27 14 UP Kushinagar 0 day Upper respiratory infection 17 11 Assam Sibsagar 13 days 18 1 West Bengal Burdwan 1 day Pneumonia 39 3 UP Gorakhpur (URI present on day 0) Typhoid fever 21 8 UP Maharajganj 2 daya Acute hepatitis 34 12 UP Gorakhpur (0 day; ill when vaccinated) Acute hepatitis and aseptic meningitis 23 2 UP Maharajganj 2 days. Causality assessment. The range of diagnoses has similarities with the fatal cases. Two clusters stand out like in the above section. They are acute encephalopathy syndrome with onset within about 3 days of vaccination, but with full recovery. The second cluster was that of acute encephalitis. While children with encephalopathy were below 7 years of age, children with encephalitis were between 3 and 12 years. Seven children were 7 years or older. The gap of interval from vaccination to onset of illness ranged from1 to 11 days. In the causality assessment, all other diagnoses, such as neurocysticercosis, hemiplegia, aseptic meningitis, bacterial meningitis, respiratory illnesses, hepatitis, typhoid fever and acute gastroenteritis have clearly alternate causative explanations and in causality assessment we consider that in our opinion, the evidence establishes absence of causal association. There were 9 cases of acute encephalitis. All except one were from Assam, Dibrugarh or Sibsagar. These districts already had JE occurring as the immunization programme was implemented (Shown in graph below. AES= acute encephalitis syndrome) and thus a clear alternate reason exists to explain the episodes of encephalitis occurring within 2 weeks of vaccination. From a causality assessment

49

viewpoint the evidence favors the rejection of causal association. Five children had onset of encephalitis 8 or more days after vaccination, including 2 with onset 11 days after vaccination. Assuming that all children had JE, it would appear that the vaccine does not protect JE while it is given during the incubation period of illness – even in the very early days of incubation period. Although we cannot attribute the rapid decline of cases to vaccination without control data, such a possibility is not unrealistic, from the shape of the epidemic curve. AES Cases & Deaths: DIB / SIB

For 9 children the AEFI was short fever. In 7 cases the onset was on the day of or within one day of vaccination. With the background knowledge that this vaccine may induce short fever as an AEFI, we consider that the evidence established a causal association. The issue of possible causal association of acute encephalopathy causing death was discussed earlier and we reasoned out why we believe that the evidence was insufficient to establish causal association. The cluster of encephalopathy cases from which children recovered has similarities of time sequence and clinical features as the fatal cases. The concentration of cases in UP (5 of 6 cases) suggests that this is predominantly a UP-centered problem. As mentioned earlier such encephalopathy syndrome occurring in seasonal clusters is well recognized in various parts of UP. There are no data to study the endemicity of this disease and if sporadic cases of the same disease occurs in non-outbreak months. In summary we consider evidence insufficient to establish causal association. Discussion and Conclusions The case records were in general of very poor quality. Except in a few cases, particularly in Karnataka, all other case records were grossly incomplete, and did not record the minimum information necessary to arrive at an evidence-based diagnosis. Progress of sick children the hospital was not noted on a daily basis.

Vaccination

0

1

2

3

4

5

6

15th

May

19th

May

23rd

May

27th

May

31st

May

18th

May

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26th

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30th

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June

11th

Jun

e

15th

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e

19th

Jun

e

23rd

Jun

e

27th

Jun

e

1st J

ul

5th

Jul

9th

Jul

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Jul

17th

Jul

21st

Jul

25th

Jul

29th

Jul

2nd

Aug

6th

Aug

10th

Aug

14th

Aug

Recovered Died

50

In most cases the doctors did not record any diagnosis and we had to piece together all clinical and laboratory data when available, to arrive at a reasonable clinical diagnosis. Thus, we have reclassified cases in order to avoid gross misclassification. One disturbing observation was to see a diagnosis “JE vaccination illness” written on many case records. While we understand the situation in which doctors were on the look out for AEFI, and every case was by definition an “AEFI” (with JE vaccine), to convert it into diagnosis is disturbing. Another observation was the wide variations in the distribution of AEFI cases by geography. This was already referred to in the earlier chapter. One such variation included the hospitalization of children with short fever, mostly in one geographic location. One could argue that it was a step for abundant caution, but such reaction on the part of doctors show the lack of confidence in their own clinical assessment of the seriousness of signs in a child who presents with fever. Without the vaccination in the background such children, or those with simple upper respiratory infection, would not normally have been hospitalized. Treatment without diagnosis was a common feature. Even when a diagnosis was recorded, treatment was inappropriate in several instances. Over-treatment with multiple antimicrobials, injected quinine and injected anti-brain-edema drugs (Mannitol) even after excluding malaria and after recording normal CSF pressure, gave away the lack of confidence of the clinicians in their own diagnostic decisions. As far as the causal association of illnesses is concerned, we observe that the number of reported AEFI was extremely small, considering the large number of children vaccinated. All AEFI were relatively common diseases which could have been part of the “background noise” of naturally occurring illnesses. Encephalitis was reported from Assam, where JE outbreak had already started. The epidemic curve of the reported cases of JE in Dibrugarh and Sibsagar districts is presented in the Figure. The timing of vaccination is also shown. It is abundantly obvious that the vaccination did not cause any increase in cases – on the contrary, there appears to have been a downward trend of cases after vaccination. However, we have not attempted to examine the issue of vaccine efficacy, for which specific studies are required. The frequency of an acute encephalopathy syndrome, mostly in UP, but also occasionally in Assam, West Bengal and Karnataka, deserves further investigations. We are aware of such encephalopathy syndrome(s) occurring in northern and central India regions over the last several decades. Even as we write this report, there are media reports of children developing an acute neurological illness with unconsciousness and death within 2-3 days. Such cases are not properly investigated or diagnosed. They go under various names, but media call it “mystery disease.” We have noted 18 such instances among these 43 hospitalized but recovered children and the 22 fatal cases. Of these 18, all but 3 had onset within 2-3 days of vaccination. Of the 18, 10 died but 8 recovered. We do not have evidence to attribute this syndrome to JE vaccination. It is possible that the injection could have triggered the illness – a possibility that needs to be borne in mind when it is investigated for epidemiology and etiology. We suspect that some pre-disposing factor could have been present and any injury or noxious stimulus could have triggered the encephalopathy attack. On the other hand, the clustering of cases could have been artifact since such cases were probably occurring as background noise. This aspect will have to be kept in mind in all future use of JE vaccine. This syndrome is more common in UP and less so

in the south (Karnataka, Tamil Nadu). It has been only occasionally reported in AndhraPradesh and Assam.

The total number of acute encephalopathy syndrome with onset within 72 hoursof vaccination was 15. There were 3 additional cases with onset beyond 3 days butwithin 14 days. Thus the total number of acute encephalopathy cases was 18. Therewere 4 children with otherwise unexplained seizures among the AEFI cases. Althoughsome had onset beyond 14 (but within 19) days, we create the 'worst case scenario' byincluding them as possible AEFI. The frequency of these cases is shown below.

Without suggesting a causal relationship of seizure and acute illnesses withseizures (acute encephalopathy) to JE vaccine, for reasons stated earlier, we highlightthe urgent need to understand more about the background occurrence of such illnessesamong children in India, and in particular in eastem UP. In future post-marketingsurveillance for vaccine efficacy and for AEFI, episodes of illnesses affecting the brainphysiology must be counted and cumulated over time and geographic space.

The frequency is so low that it would take inoculating several million doses andAEFI documentation before any meaningful evaluation of the remote possibility of atriggering stimulus can be assessed. As an interim precaution, the contraindicationslisted by the vaccine manufacturer should be adhered to, in its systematic and regularuse for protecting children against JE. We urge the Gol and UP State Government toseek help from investigators within the Health System (Medical Colleges, Indian Councilof Medical Research, National Institute of Communicable Diseases etc) to document theepidemiology and specific clinical features of this syndrome in the State and to interveneagainst any detected risk factors.

~,at~

51

Clinical condition No. Subtotal Frequency / million doses

Ac. Encephalopathy <72 hr 15 15 1.6114Ac. Encephalopathy> 72 hr 3 18 1.9337Seizures 4 22 2.3635

Chapter XRecommendations

. No direct causality has been established between the reportedillnesses and the SA-14-14-2JE vaccine. Therefore no stricture on

the further use of the vaccine is warranted.

. As has been observed case investigationsand laboratorytests 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.

. 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 using basis using epidemiological skills and expertise.

. 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.

. 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.

. 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.

~ 52

A-Nx J (1)

No. T-13020j05j2006-CC&VGovernment of India

Ministry of Health and Family Welfare(Department of Family Welfare)

.

Nirman Bhawan, New DelhiDated: the 25thJuly, 2006

OFFICEMEMORANDUM

"In partIal IT'IOdificationto this Ministry's OM of even number dated 13th July,2006, Dr. 1'. Jacob John, hof. Emeritus, Vellore Medical College has been nominated asthe team leader in place of Dr. P. Nagabhushan Rao, Pediatric Neurologist to head theNational level ComIT1ittee of Experts to review the State Investigation Reports and toInvestigate the Adverse Events following Japanese Encephalitis a.E.) Vaccination inhigh risk districts covering 4 States of the Country.

The COl1l.pOsltionof the Committee will be as under-

(1)(2)(3)

(4)(5)

Dr. 1'. Jacob John, Prof. Emeritus, Veilore Medical College - Team LeaderDr. Ramteke, Jt. Drug ControllerDr. Dlpali Mukherjee, lCMRDr. Shelh Hussain, NICD (Epidemiologist)Dr. Pradeep HaJdar, AC(UIP) - Coordinator

The Comnlittee ll1ay visit the concerned districts as and when required or asrequested by the States to review the State Investigation Reports and to Investigate AEFIcases. The TA/D.A of the officials will be borne by, their respective organizations.

. ~~~----(D.R. Sharma)..

De~'uty Secretary to the Government of IndiaPh.- en1-23062()h6

MINUTES Meeting of National Level Committee of Experts to Review “State Investigation Reports

& to Investigate the AEFI Following JE Vaccination in High Risk Districts Covering 4 States of the Country”.

A meeting was held on Friday, July 28, 2006 at 16:30 hrs under the Chairmanship of Dr.

T. Jacob John, Prof. Emeritus, Vellore Medical College to discuss the state investigation reports & to investigate the AEFI following JE vaccination in high risk districts covering 4 states of the country. List of Participants enclosed.

Committee reviewed data presented on 504 AEFI reports by Dr P Haldar followed by detail discussion. The following further analyses were suggested by the Committee to look for consistency across the data for serious AEFIs and the need for further review.

• Clinical reports of all 65 serious AEFIs reported (including 22 deaths) should be reviewed

in detail including FIR, PIR, DIR (lab, hospitalization etc). These clinical data and information are to be summarized (one page summary for each case).

• There was detailed discussion on AEFI cases (Major / Minor). Committee also reviewed the lab reports of serious AEFI. Committee felt that there is need to review the serious AEFI cases in details including case sheets / lab reports of all cases those were hospitalized.

• Classify into age slots (under fives and over fives) and compare to state-wise age-specific mortality (NSS) data.

• Also compare AEFI symptoms to other countries where SA 14-14-2 AEFI system exists (?S. Korea)

• Check the laboratory lab results for all the 65 serious cases. • “Suspected viral encephalitis” cases (n=3) deaths in Dibrugarh, should be reviewed very

carefully. • Consider classification of symptoms to consolidate variety of data on symptoms to get

some standardization of case definitions. • Look at trends over time for minor and major symptoms. • Data could be looked at by district according to ranges based on good versus not so

good reporting. Overall the Committee felt that:

• Serious AEFI cases needs further to be reviewed in detail, including the clinical notes of their hospitalization, lab reports, PIR and FIR. For this committee has requested for the cases sheets / bed side notes of serious AEFI cases for review.

• However from the data available and analyzed showed no reason for concern about the SA 14-14-2 vaccine.

• No systematic adverse events were seen • No consistency in cause of death were noted • Even statistically there were no anomalies detected.

List of Participants: Dr. T. Jacob John. Prof. Emeritus, Vellore Medical College Dr.Ramteke, Joint Drug Controller Dr.Paul Francis, WHO Dr.S.Sarkar, NTA-Polio Dr.P.Biswal, AC(I) Dr P Haldar, AC (UIP) Dr Shah Hossain, NICD Dr Dipali Mukharjee, ICMR Dr Asheena Khalakdina, PATH Dr. P Dhalaria, PATH

Record notes of the meeting

Meeting of National Level Committee of Experts to Review “State Investigation Reports & to Investigate the AEFI Following JE Vaccination in High Risk Districts Covering 4 States of the Country”.

A meeting was held on Monday, September 14th, 2006 at 2:30 hrs under the Chairmanship of Dr. T. Jacob John, retired Prof., Vellore Medical College to discuss the state investigation reports & to investigate the AEFI following JE vaccination in high risk districts covering 4 states of the country. List of Participants enclosed.

As discussed during the last meeting that a details hospital and other relevant records of serious AEFI cases will be placed before the committee. As a follow up of that, the committee reviewed data presented on serious AEFI by Dr. T. Jacab John followed by detail discussion. There was a discussion on the contents and format of AEFI committee report and following suggestions was given by Dr. John.

The AEFI report will be constitute of following chapters and the mentioned committee

member compile information on the subject mentioned against their name. Committee will review and finalize the report on 25th September, 2006 at 9:30 A.M.

Prototype for AEFI report. Executive Summary

Full Report

1. The establishment of the committee (TOR, Membership in Annexure) Dr. Haldar 2. The context of JE in India (Key References in Annex) Dr. Dhalaria 3. Vaccine against JE Dr. Dhalaria 4. The live attenuated JE virus SA-14-14-2 Dr. Ramteke 5. The licensing, procurement, storage of the live vaccine Dr. Ramteke 6. The vaccine use In the field (Training modules in Annex) Dr. Dhalaria 7. AEFI reports. Magnitude and spectrum; Investigations (Cases in Annex) Dr. John/Dr. Hossain 8. Studies in program on safety Dr. Dhalaria 9. Committees observations and conclusions Dr. John 10. Recommendations Dr. John

Annexes

• Letter of constituting committee & membership • TOR • References in JE in India • Any details in vaccines • Training /Planning/ Module • Cases line listing; Children who died etc.

List of Participants: 1. Dr. T. Jacob John. Prof. Emeritus, Vellore Medical College 2. Dr. Ramteke, Joint Drug Controller 3. Dr. P. Haldar, AC (UIP) 4. Dr. Shah Hossain, NICD 5. Dr. Pritu Dhalaria, PATH

3ITtmf ~.m. . n

~!:q[1~~IC/1

Prof. N.K. GANGULYMD,D.Se(he),FRCPath.(London),FAMS,FHA,FASc.FHASc

FTWAS(Italy), FIACS (Canada), FIMSA

Director General

~~~I~J\~ ~ ~mrI ~cTT. XI~rc1~I-{-ClII.n ~, ~ 'llTX,

~ ~ 4911, "Ii ~ - 110 029

Indian Council of Medical ResearchV.RamalingaswamiShawanoAnsari Nagar.Post Box 4911, New Delhi - 110 029

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No.30/3/2004-ECD-I Date: 08.01.2006

Dear Sir,

./ On request of the DCGI (vide letter No.JE/HLL/2005-DC, dated 26th December,2005 the dossier on Japanese encephalitis vaccine, live SA-14-14-2 was reviewed inconsultation with experts in the field in light of other infonnation available onJapanese encephalitis disease in India and development status of other vaccines andlikelihood of their availability in India.

The dossier is of a live attenuated virus (strain SA 14-14-2) based JE vaccine,. developedin China in early 1960s. No data, therefore,has been generatedregarding

non-clinical (animal) toxicology. Though WHO's Global Advisory Committee onvaccine safety in its meeting in June. 2005, has iiacknowledged the excellent safetyand efficacy profile of SA 14-14-2 vaccine", it would be essential to do 28-day animaltoxicity studies in India. This would increase the confidence level of the safety of thevaccine in face of unexpected and/or unrelated severe adverse events that may occuronce the vaccine is administered in the community. Such stuqies could be done inparallel with administration of vac~ine in the identified districts.

The vaccine has been licensed in China, Korea, Sri Lanka and Nepal, Majority of thestudies done in these countries have evaluated the SA 14-14-2 vaccine in a two doseregimen. In India, it is propos~d to give a single dose only. Therefore, it is critical toassess the level and duration of protection offered by this vaccine given as a singledose in India. Appropriate studies to address these issues would have to be designedand conducted. While the administration of the vaccine is going on in the elevendistricts in parallel following surveillance activities be carried out:

.. It is recognizedthat nutritionalstatus of the host influencesthe immuneresponse

to a vaccine. It is important,thus,to doa baselinesurveyfor diseasestatus,pre-existingJE antibody levels and nutritional status and correlate the findings withimmunologicresponse in a sub-setQfpopulationin the districtswhere the vaccinewould be given. . '

. Introduction of live attenuated vaccine virus strain in areas endemic for wild JEvirus raises the question of virus shedding and potential implications of thevaccinestrain and wild straineo-existingamongthe mosquitoestthere is an addedpotentialpossibilityof reversionof the attenuatedstrain. To monitor this aspect,virological surveillanceamong the mosquitoeswould need to be carried out inadequatesized studies.

Contd.....2

Tele,:2658820'4(Ofl.);PABX:26589334, 265893g5. 26589336, 26588707 Extn. : 264 (Res.): 26493145, 26493045Fax: 91 . 11 . 265BB662. 265B9492. 265B9647. 265B925B: E- mail : nannlllvnk{@i~mr rlplhi nil" in' n!:>nn.lh/niftn\,ro,..,.., ",ro ;"

-2-

. Epidemiology of JE is very complex and not very well understood. The selectionof districts in which the vaccine is to be used and for the above mentioned studiesto be conducted is critical to assess the results. It is essential, therefore, all theavailable JE epidemiological data is reviewed by a. group of public healthspecialists and epidemiologist to assess the suitability of their inclusion in theexercise, and suggest alternatives, if necessary.

While recommending the import of the SA-14-14-2 live JE vaccine, it is suggestedthat when the vaccine is being used in selected areas, data on its safety,immunogenicity, reactogenecity, and virological surveillance (as specified above)should be generated in the Indian population in parallel to the introduction of thevaccine.

With kind regards,

Your~sincerely,

Nci.~'~'~'

(N.K. Ganguly) ~ I (

Slu'i P. Hota,Secretary,Ministry of Health & Family Welfare,Nirman Bhawan,New Delhi-l 10 011

Copy to vimt. S. Jalaja, Add!. Secretary, Ministry of Health & Family Welfare,Nirman Bhawan, New Delhi-lID 011

C:\Documents and Settings\pdhalaria.NEWDELHI\My Documents\Nov 06 onwards data\Preliminary report - Bellary.doc, Sep 8, 2006

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An Open Label, Multicenter, Post Marketing Study to Evaluate the Safety and Immunogenicity of a Single

Dose of Live Attenuated Japanese Encephalitis Vaccine SA 14-14-2 in Children

Preliminary Report (for 28 Days Post Vaccination)

Study Site: Bellary, Karnataka

Prepared By Society for Applied Studies, New Delhi

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CONTENTS

Site investigators…………………………………………………………………………….… 03 Objectives ……………………………………………………………………………………… 04 Outcomes………………………………………………………………………………………. 04 Ethical Clearances……………………………………………………………………………. 04 Methods………………………………………………………………………………………… 05 Study sites and implementation strategy in Bellary ..……………………………………… 05 Adverse event reporting………………………………………………………………………. 06 Strategy for referrals…………………………………………………………………………... 06 Data management procedures………………………………………………………………. 07 Results………………………………………………………………………………………….. 08 Limitations of the report…..…………………………………………………………………… 10 Conclusions……………………………………………………………………………………. 10 Figure 1. Trial Profile…………………………………………………………………………… 11 Table 1. Prevalence of rare serious vaccine reactions in the first 30 minutes post vaccination…………………………………………………………………… 12 Table 2. Prevalence of adverse events in the first 4 weeks post vaccination……………. 13 Table 3. Prevalence of expected adverse events in the first 2 weeks post vaccination… 14 Table 4. Listing of adverse events in week 1 post vaccination…………………………… 15 Table 5. Listing of adverse events in week 2 post vaccination…………………………… 21 Table 6. Listing of adverse events in week 3 post vaccination…………………………… 22 Table 7. Listing of adverse events in week 3 post vaccination…………………………… 23

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SITE INVESTIGATORS VIJAYANAGAR INSTITUTE OF MEDICAL SCIENCES, BELLARY, KARNATAKA Principal Investigator Dr. J. Mariraj, Associate Professor, Department of Microbiology

Co-investigators Dr. Gangadhar Gaud, Associate Professor, Department of Preventive and Social Medicine

Dr. M Veera Shankar, Professor and Head, Department of Pediatrics

Dr. Suresh Kendri, Assistant Professor, Department of Pharmacology

SOCIETY FOR APPLIED STUDIES, NEW DELHI Dr. Sunita Taneja, Research Coordinator

Dr. Pooja Sharma, Scientist

Dr. Tivendra Kumar, Scientist

Dr. Sarmila Mazumder, Research Coordinator

Dr. Nita Bhandari, Joint Director

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OBJECTIVES - To evaluate the safety of a single dose of live attenuated Japanese encephalitis vaccine SA

14-14-2 administered in children 1-15 years of age for 28 days.

- To evaluate serious adverse events of live attenuated Japanese encephalitis vaccine SA 14-

14-14-2 administered in children 1-15 years of age for a period of 12 months post

vaccination.

OUTCOMES - Occurrence of any adverse reactions including serious adverse reactions within 30 minutes

following the vaccination.

- Occurrence of “common, minor vaccine reactions” like pain, redness, swelling, fever,

nausea, vomiting and loss of appetite in the 4 week period following vaccination.

Occurrence of “rare serious vaccine reactions” in the 4-week period following vaccination.

Rare serious vaccine reactions are adverse events that could occur with any vaccine. They

include anaphylactoid reaction, anaphylaxis, hypotonic/hyporesponsive episode (HHE) or

shock collapse, seizures

- Occurrence of unsolicited or unlisted adverse events during the 4-week period post

vaccination.

- Serious adverse events during the 12-month period post vaccination

ETHICAL CLEARANCES The IRBs of the Vijayanagar Institute of Medical Sciences and Burdwan Medical College along

with the Ethics Committee of Society for Applied Studies reviewed and approved the protocol.

Approval was also obtained from the Drug Controller General of India.

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METHODS This is a post marketing study to evaluate the safety and immunogenicity of a single dose of live

attenuated Japanese Encephalitis (JE) vaccine SA 14-14-2 in children being done in areas

where the mass JE immunization campaign of the Government of India was conducted. The

study has two components, the safety studies (in Bellary and Burdwan) and the immuogenicity

component (in Burdwan only). Informed written witnessed consent and assent was obtained

before the children were vaccinated. The evaluation of safety included daily recording of

symptoms reported by the caregiver and once daily axillary temperature measurement for 7

days post administration of vaccine. In addition to this, in the immunogenicity study baseline

anthropometry (weight and length or height) were performed and a blood sample was obtained

prior to immunization and on day 28.

STUDY SITES AND IMPLEMENTATION STRATEGY IN BELLARY

The JE immunization of the study children was done over an 8 day period (13 to 16 July 2006

and 24 to 27 July 2006) in two villages, Sangankal and Sirawara of Sangankal PHC near the

Vijayanagar Institute of Medical Sciences, Bellary.

The medical college and hospital at Bellary served as the referral centre.

Organization of a vaccination session Once a child was brought to the vaccination clinic, the parents were given the consent form for

the safety group. If the parents were willing for their child to participate they were encouraged to

ask questions. Once the investigators were convinced that the parents had understood the

study, the latter were asked to sign (or give a thumb impression) on the consent form. If the

parents were not literate, the consent process was witnessed by an impartial witness, who also

signed and dated the consent form along with the parents. If the child was over 7 years of age,

an assent was also obtained.

After the subject and parent or guardian signed the assent and consent forms, the subject was

enrolled in the study. Medical history was documented and physical examination including vital

sign assessment was performed. The subject then received the JE vaccine. After vaccination by

the ANM, the subjects were observed at the vaccination facility for 30 minutes in order to

document and manage any acute reactions.

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Follow Up Day 1 to 7: Daily home visit Subjects were contacted daily at the home or in the school, by field investigators who recorded

details of any side effects, vaccine reactions or illnesses on the appropriate forms. Any

concomitant medications were also recorded.

Day 14 (+2 days), 21(±2 days), 28 (±2 days) Home visits or contacts at school were also made on days 14, 21 and 28 post vaccination and

information on any illnesses, side effects obtained for the period since the last visit were

ascertained. Any concomitant medications were also recorded.

ADVERSE EVENT (AE) REPORTING An adverse event that came to the attention of principal investigators, supervisors and field

investigators during home visits or through spontaneous visits made by caregivers for medical

care was reported on an adverse event form. All adverse events were graded for intensity and

relatedness to the vaccine by the principal investigator or designee. In addition, each adverse

event was assessed to be serious (SAE) or not serious. For this trial, a serious adverse event (SAE) is any adverse event that results in death, is life-threatening or requires or prolongs

hospitalization or results in persistent or significant disability or incapacity.

Treatment of any AE was at the discretion of the investigator. The subjects were instructed to

contact the PI immediately should they manifest any signs or symptoms.

STRATEGY FOR REFERRALS Whenever the field investigator found that the child was ill, an adverse event form was filled and

the child was referred to the Vijayanagar Institute of Medical Sciences, Bellary. Medicines were

available to the participating children for any illness at the institute.

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DATA MANAGEMENT PROCEDURES Data Collection The field investigators manually checked the filled case report forms (CRFs) for missing

information, data range and consistency. After completion of the CRFs the field

investigator/supervisor reviewed all CRFs for completion and accuracy and filed them in each

subject Id file kept in a room with limited access. The copies of filled CRFs were either collected

by the SAS consultants during the periodic monitoring visits and brought to data management

center at Delhi for data entry or photocopied by the investigators and sent via courier to Delhi.

Data Entry, checks and Data queries In Delhi, at the SAS office two data entry clerks independently entered data in databases

created in Visual FoxPro software. Range and consistency checks were inbuilt into the data

entry system. The data files from the two data entry clerks were validated against each other for

inconsistencies and data queries generated some of which were corrected after scrutiny of the

filled data forms and those that required a clarification by the site were communicated to the

investigators via email. Once clarification from the site was available, the clarifications were

incorporated and cleaned data was merged with the main database. Two backups were made

on external hard drives and CDs.

Data Analysis Statistical analysis was performed using STATA software, version 9 (Statacorp, College Station,

Texas, USA). The proportion of children presenting with adverse events were computed.

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RESULTS The trial profile is shown in Figure1. Of the 887 children screened, 293 were in the age group 1-

5 years, 256 in the age group 6-10 years and 256 in the age group 11-15 years. The reasons for

exclusion of the volunteers based on a priori criteria are listed in Figure 1. A total of 252, 235

and 230 were enrolled and vaccinated in the age groups 1-5 years, 6-10 years and 11-15 years

respectively.

Adverse Events No serious vaccine reactions were reported in the first 30 minutes post vaccination when the

children were observed in the vaccination centre (Table 1).

No serious adverse events were reported in the 28 day period post vaccination; all adverse

events reported were of mild or moderate grade in severity.

The children were followed up by home or school visits. The number of children not available for

follow up during week 1, 2, 3 and 4 post vaccination were 2, 8, 4 and 4 respectively.

Adverse events were reported for days 0-7 (week 1), 8-14 (week 2) and 15-21 (week 3) and 22-

28 (week 4) post vaccination (Table 2). The most commonly reported adverse events were the

common minor vaccine reactions i.e. fever, pain, redness or swelling at vaccination site, nausea

or vomiting and loss of appetite. In the first week post vaccination, fever (49 children), pain at

vaccination site (26 children) and vomiting (14 children) were reported. Fever was reported by

10 children each in weeks 2 and 3, and by 5 children in week 4 post vaccination. A

Chickungunya epidemic was also reported in the state at the time of the trial. Other commonly

reported adverse events during the first week were cough (26 children), running nose (35

children), abdominal pain (10 children) and headache (15 children). These symptoms reduced

during the second week of follow up and the occurrence of complaints during this period was

cough (5 children), running nose (4 children), abdominal pain (2 children) and headache (3

children).

Fever, nausea or vomiting, and rash are mentioned in the vaccine package insert as expected

adverse events. In the first week following vaccine administration, 49 (6.9%) children reported

fever, 5 (0.7%) children reported nausea, 14 (2.0%) children reported vomiting and 4 children

reported rash (Table 3).

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In the second week post vaccination, the number reduced to 10 (1.5%) children with fever, one

with nausea and 2 with vomiting; no cases of rash were reported (Table 3).

The subject wise listing of adverse events for the first 4 weeks post vaccination are provided in

Table 4, 5, 6 and 7.

Concomitant medications During the first week post vaccination, 22 (15.8%) out of the 139 children with adverse events

received any medications. During weeks 2, 3 and 4 post vaccination, 6 out of 25, 11 out of 24

and 4 out of 14 children with adverse events received medications respectively.

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LIMITATIONS OF THE REPORT It may be noted that preparation of the report at this stage is not a part of the Project Agreement

signed with the sponsor. As a request was made to us, we have tried to comply but since

sufficient time was not available for cleaning and cross checking of data we cannot exclude the

possibility of any errors at this stage.

CONCLUSIONS Although no definitive conclusions can be made due to the lack of a control group from the data

available, the vaccine appears safe as:

- No rare serious vaccine occurred reactions within 30 minutes post vaccination

- No serious adverse event occurred during the 28 days post vaccination - Prevalence of common minor vaccine reactions and other adverse events was low

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An Open Label, Multicenter, Post Marketing Study to Evaluate the Safety and Immunogenicity of a Single

Dose of Live Attenuated Japanese Encephalitis Vaccine SA 14-14-2 in Children

Preliminary Report (for 28 Days Post Vaccination)

Study Site: Burdwan, West Bengal

Prepared By Society for Applied Studies, New Delhi

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CONTENTS

Site investigators…………………………………………………………………………….…………….. 3

Objectives ……………………………………………………………………………………… …………. 4

Outcomes…………………………………………………………………………………………………… 4

Ethical Clearances…………………………………………………………………………………………. 5

Methods…………………………………………………………………………………………………….. 6

Study sites and implementation strategy in Burdwan………………………………………………….. 6

Adverse event reporting………………………………………………………………………. …………. 9

Strategy for referrals…………………………………………………………………………... …………. 9

Data management procedures…………………………………………………………………………… 10

Results………………………………………………………………………………………….. …………. 11

Limitations of the report…..…………………………………………………………………… …………. 13

Conclusions………………………………………………………………………………………………… 13

Figure 1. Trial Profile ……………………………………………………………………………………… 14

Figure 2. Blood samples obtained at baseline……………………………………………………….. 15

Figure 3. Blood samples obtained at day 28 post vaccination……………………………………… 16

Table 1. Baseline anthropometric measurements of children enrolled in immunogenicity study…. 17

Table 2. Prevalence of rare serious vaccine reactions in the first 30 minutes post vaccination…… 18 Table 3. Prevalence of adverse events in the first 4 weeks post vaccination………………………. 19

Table 4. Prevalence of expected adverse events in the first 2 weeks post vaccination…………… 20

Table 5. Listing of adverse events in week 1 post vaccination ………………………………………. 21

Table 6. Listing of adverse events in week 2 post vaccination ………………………………………. 30

Table 7. Listing of adverse events in week 3 post vaccination ………………………………………. 32

Table 8. Listing of adverse events in week 4 post vaccination ……………………………………… 35

Table 9. Serious adverse events in the enrolled children………..…………………….. …………… 37

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SITE INVESTIGATORS Burdwan Medical College, Burdwan, West Bengal Principal Investigator Dr. Panchanan Ghosh, Professor and Head, Department of Paediatrics (June-July 2006)

Dr. Sankar Das, Associate Professor, Department of Pediatrics (w.e.f. August 1, 2006)

Co-Investigator Dr. Sabyasachi Som, Assistant Professor, Department of Pediatrics, Burdwan Medical College

Society for Applied Studies, New Delhi Dr. Sunita Taneja, Research Coordinator

Dr. Pooja Sharma, Scientist

Dr. Tivendra Kumar, Scientist

Dr. Sarmila Mazumder, Research Coordinator

Dr. Nita Bhandari, Joint Director

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OBJECTIVES Primary Objective - To evaluate the safety of a single dose of live attenuated Japanese encephalitis vaccine SA

14-14-2 administered in children 1-15 years of age for 28 days.

- To evaluate serious adverse events of live attenuated Japanese encephalitis vaccine SA 14-

14-14-2 administered in children 1-15 years of age for a period of 12 months post

vaccination.

Secondary Objectives - To evaluate immunogenicity of a single dose of live attenuated Japanese encephalitis

vaccine SA 14-14-2 administered in children 1-15 years

OUTCOMES Primary - Occurrence of any adverse reactions including serious adverse reactions within 30 minutes

following the vaccination.

- Occurrence of “common, minor vaccine reactions” like pain, redness, swelling, fever,

nausea, vomiting and loss of appetite in the 4 week period following vaccination.

Occurrence of “rare serious vaccine reactions” in the 4 week period following vaccination.

Rare serious vaccine reactions are adverse events that could occur with any vaccine. They

include anaphylactoid reaction, anaphylaxis, hypotonic/hyporesponsive episode (HHE) or

shock collapse, seizures

- Occurrence of unsolicited or unlisted adverse events during the 4-week period post

vaccination.

- Serious adverse events during the 12-month period post vaccination

Secondary - GMTs (geometric mean titers) of neutralizing antibody to the SA14-14-2 and Indian strains

of JE virus and their 95% CI

- Seroconversion and seroprotection rates with their 95% CI at baseline, 28 days, 6 and 12

months overall, by age categories and by baseline nutritional status (weight for age and

weight for height/length).

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ETHICAL CLEARANCES The IRBs of the Burdwan Medical College and Vijayanagar Institute of Medical Sciences along

with the Ethics Committee of Society for Applied Studies reviewed and approved the protocol.

Approval was also obtained from the Drug Controller General of India.

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METHODS Overview of the Study Strategy This is a post marketing study to evaluate the safety and immunogenicity of a single dose of live

attenuated Japanese Encephalitis (JE) vaccine SA 14-14-2 in children aged 1 to 15 years being

done in areas where the mass JE immunization campaign of the Government of India is

ongoing. The study has two groups, the safety group (in Burdwan and Bellary) and the

immuogenicity and safety group (in Burdwan only). Informed witnessed written consent and

assent was obtained before the children were vaccinated. The evaluation of safety included

daily recording of symptoms reported by the caretaker and once daily axillary temperature

measurement for 7 days post administration of vaccine. In addition to this, in the

immunogenicity group baseline anthropometry (weight and length or height) were performed

and a blood sample was obtained prior to immunization and on day 28.

STUDY SITES

Burdwan The JE immunization of the study children was done over two, 4-day periods (24 to 27 June

2006 and 7 to 10 July 2006) in villages of Gantar and Radhakantpur around the Memari Rural

Hospital.

Immunization Venues 24-27 June, 2006 - Gantar Gram Panchayat

- Gantar Free Primary School - Sankarpur Free Primary School - Mogra Free Primary School

7-10 July, 2006 - Mallikapur Free Primary School

- Kole Gaon Free Primary School - Kashiana Free Primary School - High School Radhakantpur The rural hospital at Memari served as the referral centre and the first storage point for the

collected blood samples which were stored in a refrigerator meant exclusively for study

samples.

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Organization of a Vaccination Session Once a child was brought to the vaccination venue, the parents were given the consent form for

the safety group. Parents who agreed to participate in the safety group were then given the

consent form for the immunogenicity group. If the parents were willing for their child to

participate they were encouraged to ask questions. Once the investigators were convinced that

the parents had understood the study, the latter were asked to sign (or give a thumb

impression) on the safety consent form if they agreed to participate in the safety group and on

both the safety and immunogenicity consent forms if they agreed to participate in the

immunogenicity group also. If the parents were illiterate, the consent process was witnessed by

an impartial witness, who also signed and dated the consent form along with parents. If the child

was >7 years of age, assent was also obtained.

After the subject and parent or guardian signed the assent and consent forms, the subject was

enrolled in the study. Medical history was documented and physical examination including vital

sign assessment was performed. A subset of 120 participants from each age category (1-5, 6-

10, 11-15 years), who had consented for participation in the immunogenicity component had 4

ml of blood withdrawn prior to vaccination for immunogenicity assessment. The sample was

centrifuged at the vaccination centre and transferred in vaccine carriers lined with ice packs to

the Memari Rural Hospital where it was kept in a refrigerator at 2 to 8° C. The serum was

transported to the Burdwan Medical College at the end of each day in a vaccine carrier lined

with ice packs and stored at –20ºC. Weights and lengths/heights were measured for the subset

of children in the immunogenicity study. The subjects then received the JE vaccine. After

vaccination by the ANM, the subjects were observed at the vaccination facility for 30 minutes in

order to document and treat any acute reactions. Any medication taken at the time of enrollment

in the study was also noted.

Follow Up Day 1 to 7: Daily Home Visit/Contact Subjects were contacted daily at the home by field investigators who recorded details of any

side effects, vaccine reactions or illnesses on the appropriate forms. Any concomitant

medications were also recorded.

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Day 14 (+2 days), 21(±2 days), 28 (±2 days) Home visits or contacts at school were also made on days 14, 21 and 28 post vaccination and

information on any illnesses or side effects obtained for the period since the last visit. Blood (4

ml) was drawn from the subjects participating in the immunogenicity trial on the day 28 visit. Any

concomitant medications received were also recorded.

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ADVERSE EVENT (AE) REPORTING An adverse event that came to the attention of principal investigators, supervisors and field

investigators during home visits or through spontaneous visits made by caregivers for medical

care was reported on an adverse event form. All adverse events were graded for intensity and

relatedness to the vaccine by the principal investigator or designee. In addition, each adverse

event was assessed to be serious (SAE) or not serious. A serious adverse event (SAE) is any

adverse event that results in death, is life threatening, requires or prolongs hospitalization,

results in persistent or significant disability or incapacity, results in a congenital anomaly/birth

defect. The SAE were also graded for intensity and relatedness to the vaccine by an

Independent Safety Monitor.

Treatment of any AE was at the discretion of the investigator. The subjects were instructed to

contact the PI immediately should they manifest any signs or symptoms.

STRATEGY FOR REFERRALS Whenever the field investigator found that the child was ill, an adverse event form was filled and

the child was referred to the Memari Rural Hospital or Burdwan Medical College. Drugs were

made available to the participating children for any illness at the Memari Rural Hospital and

Burdwan Medical College.

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DATA MANAGEMENT PROCEDURES Transfer of Filled Case Report Forms (CRFs) to SAS The photocopies of CRFs filled onsite were either collected by the SAS consultants during the

periodic monitoring visits and brought to data management center at Delhi for data entry, or

photocopied by the investigators and sent via courier to Delhi.

Data Entry, Checks and Data Queries In Delhi, at the SAS office two data entry clerks independently entered data in databases

created in Visual FoxPro software. Range and consistency checks were inbuilt into the data

entry system. The data files entered by the two data entry clerks were validated against each

other for inconsistencies and data queries generated some of which were corrected after

scrutiny of the filled data forms and those that required a clarification by the site were

communicated to the investigators via email. Once clarification from the site was available, the

clarifications were incorporated and cleaned data was merged with the main database. Two

backups were made on external hard drives and CDs.

Data Analysis Statistical analysis was performed using STATA software, version 9 (Statacorp, College Station,

Texas, USA).

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RESULTS The trial profile is shown in Figure 1. Of the 751 children screened, 252 were in the age group 1-

5 years, 252 in the age group 6-10 years and 242 in the age group 11-15 years. The reasons for

exclusion of the volunteers based on a priori criteria are listed in Figure 1. A total of 239, 244

and 237 children were enrolled and vaccinated in the age groups 1-5 years, 6-10 years and 11-

15 years respectively.

The number of children sampled at baseline in each of the three age groups is shown in Figure

2. Of the 361 children enrolled in the immunogenicity study, 116 (age 1-5 years), 118 (age 6-10

years) and 112 (age 11-15 years) i.e. a total of 346 (baseline) and 352 (28 day) specimens were

sent to NIV, Pune for analysis (Figure 2 and 3).

The baseline weight and length measurements of the children enrolled in the immunogenicity

group are shown in Table 1. The mean weights in the three age groups were 12.3 kg, 20.6 kg

and 34.2 kg respectively.

Adverse Events No serious vaccine reactions were reported in the first 30 minutes post vaccination while the

children were observed in the vaccination centre (Table 2).

As stated in the methods, children were followed up through home or school visits. The follow

up visits of 30 children were not done on the scheduled dates and data was collected

retrospectively for these children on the day of identification of the problem. The recall period for

collection of the retrospective data varied from 2 to 4 weeks.

Adverse events were reported for days 0-7 (week 1), 8-14 (week 2), 15-21 (week 3) and 27-28

(week 4) post vaccination (Table 3). Commonly reported adverse events were “common minor

vaccine reactions” i.e. fever and pain at the vaccination site. Other adverse events reported

were cough, runny nose, headache and body ache; these were most commonly reported in the

first week post vaccination (Table 3). Fever, nausea, vomiting and rash are mentioned in the

vaccine package insert as expected adverse events. In the first week following vaccine

administration 14.7% children reported fever, 2.9% children reported nausea, 2.3% children

reported vomiting and 4 children reported rash (Table 4). In the second week post vaccination

these numbers reduced to 25 children with fever, 3 with nausea, 5 with vomiting and 1 with rash

(Table 4).

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The subject wise listing of adverse events for the first 4 week post vaccination are provided in

Tables 5, 6, 7 and 8. However, these may not be consistent with the figures in the tables as

some data queries sent to the site are pending.

One serious adverse event was reported in the 28 day period post vaccination. An 11 year old

child was admitted in Memari Rural Hospital on day 5 post vaccination with a history of fall and

complaint of weakness. The child was discharged after one day without any complaints. This

serious adverse event was adjudged to be unrelated to the vaccine by the site principal

investigator and the Independent Safety Monitor (Table 9).

Another serious adverse event was reported in a child 3 months post vaccination. A 10 year old

child was admitted at Burdwan Medical College and Hospital with chronic suppurative otitis

media and a right post auricular abscess. The diagnosis of a cholesteatoma was made on CT

scan. The child was discharged after 7 days with the advice to be admitted for surgery for the

cholesteatoma. This serious adverse event was also adjudged to be unrelated to the vaccine by

the site principal investigator and the Independent Safety Monitor (Table 9). Although this event

does not fall within the 28 day post vaccination period (the interval included in this report), the

event is included as it was a SAE.

Immunogenicity The data on neutralizing antibody titers at baseline and day 28 post vaccination are not reported

as the results have not been received from NIV, Pune till date.

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13

LIMITATIONS OF THE REPORT It may be noted that preparation of the report at this stage was not a part of the Project

Agreement signed with the sponsor. As a request was made to us, we have tried to comply but

since all queries to the site have not have been completely resolved and the data are therefore

incomplete, we cannot exclude the possibility of any errors at this stage.

CONCLUSIONS Although no definitive conclusions can be made from the data available due to the lack of a

control group, the vaccine appears safe as:

- No rare serious vaccine reactions occurred within 30 minutes post vaccination

- No serious adverse event related to the vaccine occurred during the 28 days post

vaccination - Prevalence of unexpected vaccine reactions and other adverse events was low

i1

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To

Dr. P.Blswal,Asstt. Commissioner, .Ministry of Health & Family Welfare,Nirman Bhavan,New Delhi-110011.

Sir,

Please find enclosed the Final Report of the Non-clinical toxicity studies ofJE vaccine (live attenuated SA 14-14-2), conducted by NIN, Hyderabad. Alsofind enclosed the minutes of the Expert Committee Meeting to evaluate thisreport, held at ICMR Hqrs. on 16thJun~12006,

With warm regards,

Yours faJt~lfLIIlYI\,."''''

" .(,L:"\\\.,'v\j "

(Dr.Nivedita Gupta)Sr.Research Officerfor Director-General

Enc!. as above.

Copy to: Dr. Shobhan Sarkari Consultant (WR Office), Ministry of Health &Family Welfare, Nlrman Bhavan, New Delhi.

Minutes of the Expert Gl'OUpmeeting to evaluate the final report of the Nonwclinical toxicity studies of JE vaccine (Live attenuated SA-14w14.2),conducted by NIN, Hyderabad held on 16thJune 2006 at ICMR Hqrs at 10:30AM. -

Members:

Dr. N. K. GangulyDr. U. C. ChaturvedlDr. O. A. Gadkari*01'.S. O. Seth*Dr. A. C. MishraDr. 8. SesikaranDr. Dlneah Kumar

OG, ICMRChairman

Special invitee

Dr. Sarala Subbarao

ICMR Hqrs.

Dr. RashmiAroraDr. NlvedltaGupta

* Couldnot attendthe meeting

Dr. Rashmi Arora welcomed the committee members on behalf of DG,ICMR.She reqLI6stedDr. U. C. Chaturvedito chair the meeting. Dr. Chaturvedibriefed the committee of the objective of the meeting .He then requested Dr.OineshKumarfrom NIN. Hyderabadto make a brief presentationof his study.

I-Ie presented the detailed protocol and the results of the study. He saidthat a subwchronictoxicity study (28-days)was conducted in four test groups toevaluate the pre-clinical toxicity of Japanese Encephalitis Vaccine (SA 14-14-2JEV) in NIH Haliley guinea pigs. Ninety-six (48M+48F) guinea pigs wererandomizedInto 'four groups viz:,Vehicle Control (VC), Therapeutic Dose (TO),AverageDose (AD) and High Dose (HO), each group consistingof twelve malesand twel\(efemales.The dose administeredwas single and a fixed volume of 0.3ml administeredsLlbcutaneouslyto all the animalsof different test groups.

He highlighted that there were no behavioural changes in the animalsexposedto test compound.The gain in bodyweightwas not significantlydifferentbetween groups. In addition, there were.no significant differences in physicalactivitiesand physiologicalparameters.

The qualitative urine analysisdid not show any specific abnormalitiesdueto the test compound. The blood gluoose levels, kidney and liver funotlon testsevaluated biochemically were found to be normal in all groups of animalsexposedto the test compound.The hematologicalparameterswere also foundtobe within the normal range in all the groups. No evidence of immunopathologicalchanges In thymus, spleen,' bone marrow and lymph nodes was observed.Histopathologicalchanges in various organs studied did not show any significantdifferences. Immunotoxicological and genotoxicological effects were also notobserved In animals exposed to test the compound. Reactions at the site ofinjeotlonwere not observed.

Conclusions and Recommendations:

The committee examined the report submitted by NIN, Hyderabad and laterhad detailed discussion on the presentation of data by Dr. Oinesh Kumar. It wasobserved that extensive work has been done to generate a 28-day toxicity dataon live attenuated SA-14-14-2 JE vaccine in guinea pigs. The tests includedmonitoring of physical, physiological, clinical, neurological, biochemical,hematological, histopathological, Immunotoxicity and genotoxicity examinations.All the parameters were within the normal range, suggesting safety of thevaccine in this test system. However the following observations/suggestions weremade~ .

0 The results of the urine qualitative test (detects the presence of Iron),which showed positive.for blood in traces in the urine in about 20% ofanimals in all groups, could have been due to kidney pathology orextraneous factors. A detailed histopathological examination of thekidneysof all animals (includingthe ones which showed traces of blood inurine) did not reveal any abnormal histopathologicalchanges. There wasno dose dependence of the effect. In the absence of any corroborativefindings the result of this test in isolationwas not consideredto be relatedto the test compound. Therefore It appears that this finding Is of nosignificancein the experimentalsetup.

.

0 As an additionalstudy the committeerecommendedthat neurovirulenceofthe vaccine strain be tested in mice by injecting minimum 100pfudose ofthe vaccine intracerebrally.This test can be carried out at NIN, Hyderabadwith the help of NIV, Pune.

The meetingendedwith vote of tl1anksto the chair.,

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This has reference to the telephonic conversation dt. 25.9.200(1,which you had withthe undersigned, wirh relrard TOth{JITIe\1"h\5neclab~ve. It is to infonn YULIthat we have tested

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one batc.h (batch no. 20060IC004-2) of live attenuated .I.E. Vaccine, mfcl. By ChcngduInsritute of Biological Products, China, received from Dr. D. IVlanchanda. Adell. Director.Ole, Of National Vector Borne Disease Control Programme, 22-Shamnath Marg, Delhi, forthe test including Abnormal Toxicity and NVT test (copy or report enclosed, for readyreference). This batch was found to be of Standard Quality.

Another 3 batches received from Project Director CRCH)Health & Family Welfal'l.~

Ser\'ices, Bangalor~l are under test. This is for your kind information, please."/

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ToDr. D. Mllnch mln,Addilionnt Db octOI'. '

Die. or Naliol1111Vect\1\'Dome Disca~e Conti 01 Programme,22-SIIUII111nlh 'Iarg.Dclhl- 1.1QJ! 1

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Sir,

Plenserefcr lei joui'leller No.J-H.i/200G.NV(][lCP lit 2().()C).o~~.~:~~I.II:~lillgthe si'JbjecIcited above,I ." ..."

Followi",g UH.\

the lesl reHulWor' J.E VaccillE: (Livo A'l'tcllunlcd)" m!'tl. by Chall~~du Ilistitute nr DinProducl, Chill t, respectively:

I6601200G

H.esuIICDL No.

Std.Qualily

('0

,

011 lhe bnsis eir nbovo nbservnlion, lhe samples is JOll(td 10 be or :i1nmlnnl Qu.ulli.1..i

Yours H\il!Jlltl!ly

A~'Q(Dr. SuHnUt\1S)Jlgh)Addl. Dire~lo'&. HeadNo.CDL/200( ~ C:\\. 't:> _":-::''-1\ \\ "

C.R.I., Kasauli, daled lhe:(

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Copy 10; (~/-1\~~ G', ".'~F\ \ fa 9 ,.

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'Th !)rllgs Controller Genernl(l), Ole. GeneralorHefilli ~el~K~Y,Nirnmn l3hawan, New IIII 011. .

2, ; As lLjCommissioner '(1111111),Min. of Heulth & Family Wclfnrc, Nin\Ii\1I IJhawolI, New I.'. 11' 0 \ I '

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\n,No. .MLd.dt E:'{p.Dt Lobel Ab. N.V.T.I Review Toxicilyi '!

2OGOIC004..2 IS.I.O() 05.8,07 Passes PORses l'asr,cs

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IGOVERN1VIENTOF INDIA

tcrt)"1JTfT/ Telegram: 3r"j:t£c.WrT/ PRO ElLEM~'fu/Fa:c 0091.1792..272049 - 2'12016 .~'ifrt'f/Tcl: 0091-1792-272046 ..

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: '$~ 31lt5f~'1J'II ~ I~1\t"IT; CENTRAL DRUGS LABORATORYI

: ~3~m;r~i Central Research Institute; WRt-clt, ~ ~ - 173201

\ Kusauli, Himachal Pradesh, PIN 173204

\ To: Project Director CRCE),

Dte. Of Health & Family Welfare Services~Ananda Rao Circle,

0 Jl1u1~filol'e

Sub: I.tWJlg of J.E.Vnccinc {Live At1&:\l!Ul!:£!!.lJ_AEFI.Jienth (1\§.Q-=..!:£HJ.

Sir,Pleaserefer to your letterNo.RCH/V/1I2006-07dt. 15.07.06, regardingthe ~;ubje('t ciled iI\)'Y"C

Following arc the test results of lE. Vaccine (Liw Attenuated), mId. by Challgdu l1l!)t\llltc~ofUiolcProduct, China, respectively:

B.No. Mfd.dt E)i~l5tLabcl-. '~A~-'-'-T~,.V.T~' Ph~;;'~;.;:;r--""TR;Revievv' Toxicity Aspecl:.~~ ~...~,~,.. r'" ... ~.."...__..

.-,CDL No.

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..-' 1900/2006 200603C027-3 30.3.06,~~.. 1901/2006 200603C026-3 28.3.06

, , :? l.?°2/2006 700603C027:2 30.3.06L '

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On the basis of above obs(;rvation, the samples is found lQ.J:;c()f S~:,~udill1LUlillJHx

YOUI'S faithfully

Kdl ..

. (Dr. SUl'indel' Singh); Add\.Director &.Head

\ No.CDL/2006(~3 c~5'~ -<3 ,.~~~)

fl . C.R.I., Kasauh, datedthe: [Po';'t1 Copy to:g ! 1. The Drugs Controller General(l), Dte. General of Health S~)rvices,Nirman Blwwall, Nf)WIt\,~..,

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.9i}lm\§j)ioner (lmm) , Min. of Health & Family Welfare, Ninnan Hhal'vrUI,New I..~ ",,",,"':'''''' I,;'" "'~ }'"';''"'':;ti.,,,''''''''' ... 1 10011 ,,'. . .". :'''''/. ''-': ,. "'''':;';' ":.,.:,,.,.:)", .' '; I. ..., .'. . ,

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"i~~')-lJ 3T1~tErTJ'fr1T~nffiCENTRAL DRUGS LABORATORY

'~~'1I ~"fitffil ~CentralResearchlnstitute'ifi'H1-~tftT{rtr~~'~~I - 173204Kasuuli. HimachalPradesh, PiN) 73204

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I-..GOVERNMENT OF INDIA

tC'tWTff / Tel e b'fall1: 3r:b~'QR / PH. 0 B L EMtt'f'tr/ Fax: 0091-1792-272049 - 272016

~/Te): 0091-1792-272046 2 f7 Q E'

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Dr. p, Biswal,Asstt. Commissioner (hum),Ministry of Health & Family Welfare,Nirman Bhawan,New Delhi - 110011

Sub: Neut'oyirnlence Test (NVT) of J.E. Vaccine (live) mfd. By Chenudu I.ustitnh~ufBiolutJical ,Products. ~hina - reg..

Sir,

This has referenceto the tele.B!1onlcconversationctt.25.9.2006,which you hadwiththe undersigned,wilh regardto th{JmeY1t'bnedabove.It is to informYOllthatv,;ehavetestedone batch (batch no, 200601COO~-2)of live attenuated'1.E. Vaccine, mfd. By ChengduInstitute of Biological Products, China, received from Dr, D.Manchanda, Add\. Dimctor,Dte. Of National Vector Borne Disease Control Programme, 22-Shamnath Marg, Delhi, forthe test including AbnormalToxicity and NVT test (copy of report enclosed. for readyreference), This batch was found to be of Standard Quality,

Another 3 batches received from Project Director (RCH) Health & Family \VelfareServices, Bangalorefare uncler test. This is for your kind information, please.

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...J:.V\.'\'~i'(~.{1------.(Dr. Surillc1er Singh)

Addl. Director & I-lead

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IWf) ,Marti ~~lirnpl~$ lrm'l"\ C1;;\$~\:iadll'\{\.t{~KI~1t 8RD M~clicr.ll C:~ollega and 6 !:i!:)\"e~,~~imH:}Ii;1B,,'rom L,JttarPrw\I~$lhPUblicHa2Jltl.team Wl'ht'€'receivuHt One vial of CSF. ,~v'I:\:I; ti~rnr,;)ty~m(j In ('jI"\I;'!the quantity "was vm'y low.

A~j per th~l In5lructlon~ r~~ct'ilV~dfroni Director Centilrol, ICMR loIlOWII'\.9\!:\~)t1:i'W't)t{iJ1~(;IITlfJ(~out on 'th<:JBe sarnple.s.

1. De\ac.\iQr1 C)'f 19\\)1 UH'i\ibodi~tj ~\gej\nfjl J[ virilo Liy 1~1v1t:U'im~o\Jy

L;nmur~J'::lI$AFtr PCH on CSF 'BHrnpIEH'1for det0Jction of .H:.vlrW$genQrnf;l

Ilio{:ulaUan <.')fCSF eamplaa ir\ BHI'\ OUll6 for deteotlonof viruugrowthReal Tin\f~ PCI:< 'fcw del€mti('j)''1 or ,Jt: viruf::glarJomeIn CSr:Garnpl~s .

I Il WHISO\"JiiOr'VOl'ltliat IgManti.JEviru~sntibmjlee wel~ nut dat~cti:'ll)lein '14QUI: of "Iej CSI~ sarnple6 t~::;tad. TINO CSI~ SarnplfJUi showed very lOw\)\)('\h~i'\In!;1rEHil'~tlviWwill't JE VIrYs, In butt\ ca(J\-)U Qnaet of symptoms \':ieJ per

tI\1:I d~\~ provld!;'\d W~8 " {.,nci 2 (jay~ post v~wcirH~l!\'}n, lienee th$~$antil:.JOdlet~may not b0 rf:)I<~nt:Jclto vacclll~lI()n

~. I~T.I:';CF'~ u~ln~Jnr~viviru~ ilJpecltic Pi'!lYWJI'Pi!llt~~wel'G can-ilid out on all CSF~arnplaH. NfJr1filof U,n $J:'HnfJJtJ~~1~low~dpr~~0n,,(!Jqf J\;~vlrw~F<NA,r::wther,nested r:ICR WCijt-~)h,m o~1n'iv)d O\.lttor InQr~m~ec.1g,ent3i\ivlty\andnon~ a"ftl"le!1fH'npl~~sSI'\LNJ~H~pr~senoec)lJE Ylrus,genQmes. 80th JE virw.i al"td SA 'I(.~-

"14-2virus ~:Qntr(llsCL1UIdbfi d$H;Qt~d ~J$1I1QlIltHiHiJprimer p~jr$,

:3 All CSF 8~1rnplaawer~ inoculated In BH~\ W~~1I3trlt1i are sanai8tiva to bOU1WII(j tYPC1J'E and att~tl'\llat(~d.JE ViI'LI~,All tht~l culturesware (.1~1$(:jNed lor

mQrethan t1 day~. No f.jjQlw,01' cUlYGylopclU"lioGfffJolindicmtingvlrufJfJI'OwthW\')I'Gol:J$olval:1 .,

4, l\jon~ or tt'I~,)GUrnp(61~&1'low~I(.i~ny Glgn@1fCJf'\)anUrrH'j~)'fJE. virusInUlaCSFS~3rnple$by F,~~~I'rima P(";H,

rn~ test!:! ind(C6ttGdtl'lat tl'1ti:)~arnpil% i'~Ci~\v.oddid lifJl ~h\J\t1lpl'~$(;Jnce O'{'wil!:1type\;1' vt~!~eil1~'.m vln.J13

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T Jacob John, MBBS, DCH, FRCP(E), FRCPCH, PltD, DSc, FAMS, FNA.

Past President, Indian Association of Medical Microbiologists, 1994Past President of India" Academy of Pediatrics, 1999

439 Civil Supplies Godown Lane, Telephone: 0416 226 7364Kamalakshipuram, Vellore, TN, 632 002. Email: vIr tiiohn@sancharnetin

Shri P K Hota, IASSecretary,Ministry of Health & FW,Government of India, New Delhi.

20 October 2006

Sub: AEFI of JE vaccinationRef: No. T-13020/0512006-CC&V Dated 25thJuly 2006.

Dear Mr Bota,

The Committee of Experts has studied in detail the documents on AEFI in 11Districts of 4 States where the live attenuated JE SA-14-14-2 virus vaccine was given tochildren. I have pleasure in submitting the Report.

We have not found any evidence to conclude that any of the reported illnesseswere caused by the vaccine. However, thyre is a background of childhood illnesses thatdeserve to be investigated in their own rights - both for the health and survival ofchildren and to remove them from the confounding effect they pose when large numbersof children are followed up after any vaccination.

Thank you very much for reposing your confidence in the members of theCommittee.

Yours faithfully,

~u(7uw,

T Jacob JolIn,Team Leader (on behalf ofthe Expert Committee)