2006 report. Issued in the public interest

1. 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
1

2. 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,
2

3. 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
3

4. the Program for Appropriate Technology in Health for their assistance and
support to the work of the Committee. As Team Leader it is my duty to thank the
members of the Committee who have patiently and diligently gone through all the
available data and helped in arriving at clear conclusions as well as for drafting
several chapters.
;;
~
T Jacob John 5 October, 2006
Team leader
t
4

5. 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
5

6. 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.
6

7. 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.
7

8. 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
8

9. • 1955: JE virus isolated from brain biopsy at Vellore. Virology conducted at Virus
Research Center at Poona (now National Institute of Virology, Pune)
• 1950s and 1960s. Identification of vectors as Culex vishnui complex; pigs found to
be amplifier host; cattle and humans found to be non-amplifier hosts.
• 1960s. JE detected in Andhra Pradesh and Karnataka
• 1973: Outbreak reported from Burdwan & Bankura districts, West Bengal.
• 1980s. JE caused outbreaks in Assam Bihar and eastern UP, moving westward in
subsequent years to Delhi and Haryana.
• 1990s. JE in Maharashtra, Goa and Kerala.
Disease burden and reporting:
JE has since been reported in 26 States and Union Territories (UTs), especially 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. Affected States /
2002 2003 2004 2005
No. Union Territories
C D C D C D C D
1 Andhra Pradesh 22 3 329 183 7 3 0 0
2 Assam 472 150 109 49 235 64 145 52
3 Bihar 8 1 6 2 85 28 192 64
4 Chandigarh 4 0 0 0 0 0 0 0
5 Delhi 1 0 12 5 17 0 2 0
6 Goa 11 0 0 0 0 0 3 0
7 Haryana 59 40 104 67 37 27 0 0
8 Karnataka 152 15 226 10 181 6 75 6
9 Kerala 0 0 17 2 9 1
10 Maharashtra 119 16 475 115 22 0 66 30
11 Manipur 2 1 1 0 0 0 1 0
12 Punjab 10 2 0 0 0 0 0 0
13 Tamil Nadu 0 0 163 36 88 9 8 1
14 Uttar Pradesh 604 133 1124 237 1030 228 6096 1511
15 West Bengal 301 105 2 1 3 1 6 1
Grand Total 1765 466 2568 707 1714 367 6594 1665
C = Cases D = Deaths
9

10. 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
2
clusters of cases were evident in three different municipalities’ viz. Chidambaram, Virudhachalam and Thittakudi.
3
ICMR report on Japanese Encephalitis
10

11. 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.
11

12. 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
12

13. 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.
13

14. 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
14

15. 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
15

16. 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.
16

17. 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-
17

18. 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
18

19. 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
19

20. 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.
20

21. 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.
21

22. 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.
22

23. [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
23

24. 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.
24

25. • An operational guide and training module was developed.
• A Sensitization & Planning workshop with representatives from five States (UP,
Assam, West Bengal and Karnataka and CMOs and DIOs of 11 districts was
held on 30-31st January, 06 under the Chairpersonship of AS (J).
• A time line for implementation of vaccination campaign was worked out and the
vaccination campaign started from 15th May, 2006.
• District level task force meeting, chaired by the District Collectors of all 11
districts was held.
• Micro-plan for JE vaccination campaign at the district level was prepared.
State / Dates for Campaign District
Kushinagar
Gorakhpur
Maharajganj
Uttar Pradesh
Deoria
(15th May 06)
Kheri
Sidhartnagar
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 National Vaccine
(Parallel) testing of dose in
samples) Million
12- Apr 12-May 5.2
19- Apr 19-May 2.5
09-May 09-June 4
30-May 30-June 1.8
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 Vaccine Requirement
(Doses) (Doses) in Million
Uttar Pradesh 6140616 + 2225916 6.14 + 2.3
West Bengal 2957133 2.95
Assam 955663 0.95
Karnataka 865488 0.86
25

26. 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
26

27. • Coordination
o Specific instructions and date of activity in the village/ ward should be
communicated to school authorities at least 14 days prior to the activity by
the District Education Department
o Instruction must include specific job responsibilities of school teachers &
students in the activity
o Respective departments should intimate their functionaries at the village
level of the date of the campaign for that village and assign specific
responsibilities two weeks prior to the program
o DTF will ensure that instructions and guidelines have been sent out from
the District level
o BTF will ensure that the instructions have reached the target
functionaries.
Estimation of Beneficiaries
o All children between the age group above 12 months and below 15 years
should be estimated for vaccination with JE vaccine
o It is estimated that the above age group will constitute about 33 % of the
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
27

28. o JE Vaccine
o Reporting coverage
o AEFI – actions to be taken, referral & reporting
o Waste disposal following vaccination
o JE Vaccine
- Freeze dried, Needs to be reconstituted with the diluents provided
with the vaccine (Phosphate Buffer Solution)
- Heat sensitive.
- Storage and transport at 2-8°C
- To be used within 2 hours of reconstitution
- Single dose – 0.5 ml ( irrespective of age group)
- Subcutaneous 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
28

29. Recording and reporting
o All formats to be used as mentioned in operational guideline.
Coverage data
Target Children No. of Children % Beneficiaries
(1-15 years) vaccinated vaccinated
99.01
Koshi Nagar 1095877 1085055
97.03
Gorakhpur 1390307 1349047
103.93
Maharajganj 776500 806996
99.86
Deoria 1074219 1072683
102.95
Lakhimpur-Kheri 1183481 1218364
94.35
Sant Kabir Nagar 542062 511417
94.35
Siddharth Nagar 775934 792944
99.97
UTTAR PRADESH 6838380 6836506
56.12
Burdwan 2190690 1229404
56.12
WEST BENGAL 2190690 1229404
90.49
Dibrugarh 409611 370653
74.25
Sibsagar 372356 276487
82.76
ASSAM 781967 647140
82.67
Barelli 720517 595648
82.67
KARNATAKA 720517 595648
88.39
INDIA 10531554 9308698
29

30. 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.
Completely
AEFI
Children recovered
cases Hospitalized Death
vaccinated without
reported
hospitalization
4
Koshi nagar 1085055 18 11 7
2
Gorakhpur 1349047 85 71 14
1
Maharajganj 806996 50 42 8
0
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
7
UTTAR PRADESH 6836506 222 192 30
6
Burdwan 1229404 24 16 7
6
WEST BENGAL 1229404 24 16 7
3
Dibrugarh 370653 49 38 11
4
Sibsagar 276487 66 53 13
7
ASSAM 647140 115 91 24
2
Bellary 595648 143 140 2
2
KARNATAKA 595648 143 140 2
22
INDIA 9308698 504 439 63
30

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 438
2. UIP Section Serious Recovered 43
3. Death 22
4. GOI team in UP Additional names from Gorakhpur Line List 30
Total AEFI 533
AEFI cases and deaths in 11 districts and 4 states
following JE immuniz ation
AEFI de aths , 22,
4%
AEFI r e quir ing
hos pitalization
but im pr ove d,
43, 8%
AEFI r e quir ing
no hos pital car e ,
446, 88%
31

32. 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 12
Maharajganj 17-May 29-May 13
Kushinagar 15-May 25-May 11
Kheri 15-May 26-May 12
Sant Kabirnagar 23-May 29-May 7
Siddharthnagar 20 May NA NA
Deoria 15-May 29-May 15
Gorakhpur 15-May 27-May 13
Bellary 10-Jul 15-Jul 6
Dibrugarh 2-Jul 15-Jul 14
Sibsagar 2-Jul 14-Jul 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
Other
Fever Fever Fever Neuro
District immediate < 3 d > 3 d Vomiting Convulsion Sign ARI Rash
Burdwan 12 2 1 9 3 2 5 3
Maharajganj 14 7 3 16 4 3 0 3
Kushinagar 5 3 4 4 7 5 1 2
Kheri 1 10 1 1 0 0 0 7
Sant Kabir 2 0 0 2 0 0 0 0
Siddharth
nagar
Deoria 24 0 1 12 1 0 9 0
Gorakhpur 25 15 8 26 12 4 4 10
Bellary 54 1 1 20 3 2 1 26
Dibrugarh 10 7 10 19 8 3 1 2
Sibsagar 17 34 9 16 8 7 2 0
164 79 38 125 46 26 23 53
32