Causality assessment of adverse events following...

SEA-Immun-88

Distribution: General

Causality assessment of adverse

events following immunization

Report of an intercountry workshop

18–20 February 2014, Bangkok, Thailand

ii

© World Health Organization 2014

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Contents

Page

Acronyms .............................................................................................................. v

Executive summary ............................................................................................... vi

1. Background ................................................................................................... 1

2. Methodology and objectives .......................................................................... 4

3. Proceedings ................................................................................................... 7

Annexes

1. List of participants ....................................................................................... 15

2. Agenda ........................................................................................................ 18

3. Summary country profile, status of AEFI and performances of vaccine

pharmacovigilance systems .......................................................................... 19

4. Case Study AEFI investigation report ............................................................ 24

5. Eight AEFI case reports with findings of working group and summary of

plenary discussions ...................................................................................... 26

6. Questionnaire to assess usefulness of causality algorithm tools to

participants ................................................................................................. 52

7. Plenary discussions ...................................................................................... 58

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Acronyms

AEFI - Adverse Events Following Immunization

NIP - National Immunization Programmes

NRA - National Regulatory Authorities

EPI - Expanded Programme on Immunization

LIC - Low-Income Countries

VPD - Vaccine Preventable Diseases

NCL – National Control Laboratory

CIOMS - International Organizations of Medical

HMIS - Health Management Information System

SIDS - Sudden Infant Death Syndrome

LMIC - Low and Middle-Income Countries

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Executive summary

The World Health Organization (WHO) Regional Office for South-East Asia

organized an intercountry workshop on causality of adverse events

following immunization (AEFI) from 18 to 20 February 2014 in Bangkok,

Thailand, as part of the regional strategy to support countries to strengthen

national vaccine safety surveillance and AEFI monitoring systems. Since

2008, WHO has provided training support to national regulatory authorities

(NRAs) and national immunization programmes (NIPs) in the South-East

Asia Region to strengthen capacity to detect, report and investigate AEFI.

WHO training material is utilized in all countries to conduct training

programmes. These programmes are adapted to local needs by national

immunization programmes and national regulatory authorities and National

AEFI committees for peripheral level immunization service delivery and

may be translated into local languages in some countries. WHO provided

follow-up support to some countries to establish national AEFI committees

and their secretariats, update national guidelines, implement pilot projects

to test and validate notification forms and investigation templates, and to

standardize data analysis and reporting. The countries of the South-East

Asia Region have thus experienced enhanced reporting of AEFI cases for

which the causes were not always understood. This resulted in unnecessary

concerns and disrupted routine immunization programme for some

vaccines in some countries.

As part of the strategy to address this risk of loss of public confidence

in the immunization programmes, the countries in the South-East Asia

Region strengthened their national AEFI committees with new members

with expertise in neurology, forensic specialists, paediatricians,

epidemiologists and professors in teaching hospitals. WHO proposed to

organize this intercountry workshop involving 29 vaccine experts from ten

countries in the South-East Asia and Western Pacific Regions to review,

discuss and analyse selected cases of AEFI for the period 2011–2013. WHO

country offices were instrumental in mobilizing national AEFI committee

members to identify specific AEFI case reports for discussion. Six out the ten

participating countries provided a total of 23 AEFI case reports. Not all

cases submitted could be reviewed because of time constraints and so nine

cases were short-listed and anonymized for the purpose of this workshop.

In addition to South-East Asia Region countries, Viet Nam in the WHO

Western Pacific Region participated in the workshop.

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The workshop provided a platform for experts in each country to

share their experiences and report on their performances in an open forum

with presentations using standardized templates. The new definitions for

AEFI and vaccine pharmacovigilance were presented and discussed in

plenary sessions. The WHO revised causality assessment methodology was

further tested in the process of reviewing selected cases and participants’

opinions on the usefulness of the tool were collected through a

questionnaire developed during the workshop. Participants appreciated the

opportunities to discuss with experts from different fields and learned a

great deal by working on AEFI case reports in the Region. All countries

acknowledge the need for further collaborative initiatives like this workshop

in the field of vaccine pharmacovigilance and developed a set of

recommendations to foster increased cooperation among countries in the

Region and beyond.

1

1. Background

The Expanded Programme on Immunization (EPI) was established in 1974

at a time when only 5% of the world’s children were protected by

vaccination against six diseases, that is, polio, diphtheria, tuberculosis,

pertussis, measles and tetanus. Today, that figure is 83%, with some low-

income countries (LICs) reaching 99% immunization coverage.

Consequently, some vaccine preventable diseases (VPDs) are today on the

verge of eradication. The challenge for immunization programmes

throughout the world has become to maintain high immunization coverage

with VPDs disappearing from the collective memory. Vaccines are the safest

medicines with very rare serious adverse events following immunization

(AEFI). Although, serious AEFI are in the range of 1 per million doses, public

tolerance is much lower than for medicines because vaccines are given

mostly to infants who are healthy at the time the vaccine is administered. In

addition, vaccines are provided to children less than one year of age, a

vulnerable age in many LICs. A country with an infant mortality of 50 per

1000 live births may expect 14 deaths of children below one year every

day. As vaccination is routinely provided, those deaths could be attributed

to the vaccine when in fact they are coincidental and are due to

underlining diseases which were not diagnosed at the time of the

vaccination. Thus, it is essential to sustain public confidence in

immunization to establish surveillance systems that detect and report AEFI

in the national immunization programme (NIP), experts committees able to

conduct scientific AEFI causality assessments and ministry of health capacity

to address vaccine safety concerns.

The World Health Organization (WHO) has a long history of technical

support to build the national capacity of Member States in the South-East

Asia Region to monitor AEFI. In 2003, the WHO Regional Office for South-

East Asia established the Global Training Network (GTN) centre in

Colombo, Sri Lanka to provide training on AEFI monitoring to South-East

Asia Region Member States and to other WHO regions. The GTN centre in

Sri Lanka was instrumental in providing training on AEFI monitoring to

national regulatory authority (NRA) and EPI representatives of the countries

of the South-East Asia Region.


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Meanwhile, NRAs have initiated capacity-strengthening activities to

meet international/WHO standards for vaccine safety, quality and efficacy.

In the South-East Asia Region countries, national expertise increased and

new requirements emerged to further expand the basic AEFI course in

order to meet training requirements with new more complex vaccines and

additional experts added to the national AEFI committees. The WHO

course content of the basic AEFI training package was revised to cater to the

needs of national AEFI committees as they were being established by

NRAs/national control laboratories (NCLs) and NIPs with pharmacists,

experts in allergies, forensic specialists, professors in immunology, etc. who

were not always knowledgeable about their national vaccine safety

surveillance system.

To further support AEFI causality assessment, the revised AEFI training

material was tested in 2012 in Myanmar and Nepal with participants from

national AEFI committee members, NRA representatives and EPI managers.

In Myanmar1

, the training methodology was adapted to maximize time for

participants to breakup in small groups to conduct formal causality

assessment of selected AEFI cases. Analyses of cases were reviewed in small

working group sessions using the WHO 2012 revised causality assessment

methodology for causality association and the findings were debated in

plenary sessions to reach consensus on the conclusions of the committee

about the causal association of the vaccine with the symptoms.

Since 2008, the Regional Office for South-East Asia has conducted 11

training workshops on AEFI monitoring in eight countries of the South-East

Asia Region, that is, Bangladesh, Bhutan, Democratic People’s Republic of

Korea, India, Indonesia, Nepal, Myanmar and Sri Lanka. The Regional

Office for South-East Asia support toward training on AEFI2

is a two-

pronged approach to address needs in the NRA capacity strengthening

programme

(1) for vaccine pharmacovigilance and the building of national AEFI

committee with national AEFI experts to periodically review cases

________________________ 1 Report on the Training Workshop on Adverse Events Following Immunizaton 26–30 April 2012, Nay Pyi Taw,

Myanmar. Report available within Regional Office for South-East Asia/FHR/IVD library.

2 Adverse Events Following immunization in the South East Region 2008–2010; Report on WHO support to

training programme.

Causality assessment of adverse events following immunization

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of AEFI and to respond scientifically to serious AEFI cases and

concerns of vaccine safety and;

(2) to improve the detection and reporting of AEFI, including to

update monitoring guidelines and implement pilot projects with

enhanced AEFI surveillance systems to validate notification forms

and reporting mechanisms.

Consequently, AEFI cases which were neither detected nor reported

before AEFI strengthening activities have started to be increasingly detected

and reported to national AEFI committees. Several countries have established

surveillance systems that not only detect serious AEFI cases which result in

hospitalization but also detect minor AEFI cases.

In the South-East Asia Region, the countries are introducing or have plans

to introduce new vaccines in their NIPs; therefore, programme managers along

with regulators and the members of national AEFI committees, and other

national vaccine safety stakeholders in South- East Asia, identified the need to

strengthen procedures to investigate and analyse AEFI cases in a systematic and

scientific manner in order to provide timely and accurate responses to address

errors to help immunization providers and the public at large. Strengthened

procedures will also address vaccine safety concerns.

Countries in the WHO Western Pacific Region identified similar training

needs following recent allegations concerning vaccine safety that resulted in

temporary suspension of specific immunization programmes until further

findings could reject a causal association with the vaccine in question. The

South- East Asia and Western Pacific Regions share the same suppliers for most

of the vaccines for their NIPs, making vaccine safety a cross regional issue

requiring mechanisms to share information and analyse cases for causality

assessments. In this connection, both regions have been cooperating to

undertake joint efforts and to initiate joint activities on vaccine safety

surveillance and AEFI monitoring when possible. Regional and intercountry

workshops agendas are designed to address training needs in the two regions.

As of 2009, all countries in the Regional Office for South-East Asia,

except Maldives and Timor-Leste, had established a national AEFI committee

to review and analyse AEFI cases on a periodic basis. Thus the time was ripe

for an intercountry workshop on causality assessment to share learning and

discuss experiences with the currently recommended tools and processes.


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This intercountry workshop on causality of AEFI conducted in

Bangkok, Thailand, from 18 to 20 February 2014 was primarily aimed at

countries with an established surveillance system (to detect and report AEFI)

supported by a national AEFI committee that meets regularly to conduct

AEFI causality assessments. The session plan of the standard WHO five day

advanced course on AEFI monitoring, investigation and causality assessment

was adapted to a three-day agenda focusing predominately on causality

assessment. The training methodology emphasized working group sessions

to stimulate discussions and exchange of experience and also to create a

work environment similar to a meeting of an AEFI causality assessment

committee which would meet to review and to determine causes of

selected cases of AEFI. The 29 participants were from Bangladesh, Bhutan,

India, Indonesia, Maldives, Nepal, Sri Lanka, Thailand and Timor- Leste in

the South-East Asia Region and Viet Nam in the West Pacific Region. They

included representatives of national AEFI committees, NRAs and NCLs, EPI

managers, hospital paediatricians and professors from university and

medical institutes and two WHO country office representatives from India

and Nepal. (See Annex A for List of participants.) The intercountry

workshop was facilitated by Professor Noni MacDonald, Professor of

Paediatrics, Dalhousie University, Halifax, Canada; Dr Ananda

Amarasinghe, Consultant epidemiologist, Epidemiology Unit, Ministry of

Health, Sri Lanka; Dr Madhava Ram Balakrishnan, Medical Officer,

Quality, Safety and Standards, WHO Geneva and Mr Stephane Guichard,

Regional Adviser, Vaccine Supply and Quality, WHO Regional Office for

South-East Asia.

2. Methodology and objectives

2.1 Objective

The main objective of the workshop was to build regional capacity to

assess AEFI with the following specific objectives:

to review selected AEFI cases from 2011–2013 in the WHO

South-East Asia and Western Pacific regions using WHO revised

the methodology for causality assessment;

to identify critical AEFI cases of common interest for countries of

the South-East Asia and Western Pacific regions (serious and


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non-serious AEFI) to standardize terminology and case

definitions to enable comparison and also signal detection by

aggregating data from several countries;

to streamline AEFI data collection procedures by introducing

core variables and data analysis methods;

to apply the new WHO causality assessment tool in different

country settings, in order to strengthen its wider application; and

to set the prerequisites for sustainable regional collaboration to

share vaccine safety data of regional and global importance.

The agenda was spread over three days with the first day centred on

sessions for country presentations by national counterparts to inform the

participants about the status of vaccine pharmacovigilance system in their

countries and activities to strengthen detection, reporting and analysis of AEFI

cases (The agenda of the intercountry workshop is shown in Annex B)

2.2 Methodology

Prior to the workshop, the countries were contacted by the WHO Regional

Office and country offices to provide a standard presentation template to

report on the current status of vaccine safety surveillance systems, activities

of the national AEFI committee and current constraints and opportunities.

Initially, countries presented their situation analysis, enabling participants to

gain understanding of the various country scenarios. Then the audience was

updated on the recent Council for International Organizations of Medical

Sciences (CIOMS) definitions and the concepts of vaccine

pharmacovigilance in order to facilitate harmonization of procedures and

data-sharing and data mining. Definitions and classifications of AEFI were

updated by the CIOMS/WHO working group established in November

20053

to develop general definitions strictly focused on vaccine

pharmacovigilance and to contribute to the development review evaluation

and approval of definitions on AEFI as developed by the Brighton

Collaboration process and to their dissemination.

________________________

3 http://vaccinepvtoolkit.org/vaccine-wp/wp-content/uploads/2013/12/report_working_group_on_vaccine_LR-

CIOMS-WHO-WG.pdf

http://vaccinepvtoolkit.org/vaccine-wp/wp-content/uploads/2013/12/report_working_group_on_vaccine_LR-CIOMS-WHO-WG.pdf

http://vaccinepvtoolkit.org/vaccine-wp/wp-content/uploads/2013/12/report_working_group_on_vaccine_LR-CIOMS-WHO-WG.pdf


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The second day was devoted to the review of selected cases for AEFI

causality assessment. Participants were divided into three groups. Each group

was given three AEFI cases which had occurred in the South-East Asia Region

between 2011 and 2013. Several weeks before the meeting, chairmen of the

national AEFI committees in the South-East Asia and Western Pacific Regions

were contacted by WHO country offices to provide a minimum of five AEFI

investigation reports. A total of 23 AEFI investigation reports were provided by

six of the 10 countries represented at this workshop. Each AEFI investigation

report was then anonymised by removing names of the case and other

identifiers including name of institutions and addresses. Once the cases had

been anonymised, nine were selected by the facilitators. Selection criteria

included cases with well-documented reports and cases with AEFI known to be

linked to vaccines. The cases were then numbered from 1 to 9 and each

working group received three of these case reports to review and to present

the outcomes of their analysis in plenary. Two groups managed to review all

their assigned cases with one group reviewing only two cases. The participants

therefore, analysed eight cases and presented their findings in the plenary

sessions.

On the third day, following presentations on vaccine pharmacovigilance

global initiatives, the workshop provided a platform for participants to discuss

and provide comments on the different tools recently developed by WHO to

conduct causality assessment, including the revised causality assessment

methodology, the AEFI core variables, sample reporting forms and supporting

materials available on the web. It was an opportunity to have representatives

from national AEFI committees, NCLs and NRAs meet together to discuss

important questions, such as the need to (1) establish a regional/biregional

group of experts to respond to serious AEFI cases which could have public

health impacts that occur in countries with limited capacity; (2) analyse

regional data with particular interest in signal detection; (3) explore how to

sustain national vaccine pharmacovigilance systems and to increase

involvement of academicians and medical colleges and institutes involved in

postmarketing vaccine safety surveillance; and (4) discuss what countries saw

as the regional needs for monitoring AEFI and maintaining public confidence in

immunization programmes.


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3. Proceedings

3.1 Vaccine pharmacovigilance systems

Nine countries from the South-East Asia and one from Western Pacific

regions presented their AEFI surveillance and causality assessment systems.

Annex 3 summarizes country profile, status and performance of the vaccine

pharmacovigilance systems in each country.

Of the 10 countries, only Maldives and Timor-Leste do not have yet an

established AEFI surveillance system with a national AEFI committee. Of four

vaccine-producing countries, Thailand reported more than 1000 AEFI cases.

Indonesia in the last three years has significantly improved its capacity to detect

AEFI with more than 18 000 reports in 2013. The two other vaccine-

producing countries, that is, India and Viet Nam respectively reported 536

cases and 31 cases in 2013, highlighting significant under-reporting occurring

under these systems. During the plenary discussions, India explained that the

figures included only severe AEFI; the nonserious AEFI are monitored through

the health management information system (HMIS) and were not included in

the India presentation.

Nepal and Sri Lanka are among countries that procure vaccine directly

except for pentavalent DPT-HepB-Hib vaccine which is procured through

UNICEF. Nepal, with its nascent system, reports fewer than 30 AEFI cases a

year, whereas Sri Lanka has a well-established AEFI system and reports more


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than 6400 cases per year. In the other countries that procure vaccine through

UNICEF, that is, Bangladesh, Bhutan and Timor-Leste, the capacity of the

surveillance systems to detect and report AEFI varies widely. Bangladesh, which

has plans to produce vaccines itself, has shown significant progress with more

than 2200 cases reported per year. The other three countries report only

serious cases, that is, hospitalizations and deaths. In 2013, Bhutan reported 16

cases, Maldives no cases and Timor-Leste one case. These countries have

relatively small populations and may not have a serious AEFI at all for several

years. Thus, it may not be sustainable for them to maintain a full-fledged

system with national AEFI committee to detect very rare events and then carry

out causality assessment on serious AEFI, and a rapid response system might be

more suitable. However, these countries as well as all the others were

encouraged to monitor nonserious AEFI which could help to detect

programmatic errors and/or signals.

Progress is most significant in the capacity of the countries to analyse AEFI

data. The cornerstone of vaccine pharmacovigilance is the national AEFI

committee that collects, consolidates, reviews and analyses AEFI data to

conduct causality assessment. All participating countries except Maldives and

Timor-Leste have established a national AEFI committee. India is the only

country that has a secretariat for the national AEFI committee, officially

established in 2012. All the national AEFI committees were reorganized in the

last three years to address the increasing number of AEFI to be reviewed

because of improvement in AEFI surveillance systems. The national AEFI

committees, however, do not meet regularly in all countries, which results in a

substantial number of serious cases not being reviewed in a timely fashion. In

2013, India managed to review 30% of serious cases while Bangladesh

reviewed only 27%. On the other hand, the national AEFI committees of

Indonesia, Nepal, Thailand and Viet Nam managed to review all the serious

AEFI cases reported in 2013.

Out of 10 countries, four listed poor quality of data as a major constraint

and three mentioned high staff turnover. Finally, six countries reported

difficulties in sending the investigation team to the field within 24 hours and

their lack of training in AEFI field investigation.

The country presentations were followed by a series of lectures to review

causality assessment. Dr Madhava Ram Balakrishnan presented the revised

WHO causality assessment methodology including the revised CIOMS


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definition of AEFI. The latter raised concerns among the participants, especially

with the term “unfavourable”.

AEFI is defined as any untoward medical occurrence which follows

immunization and which does not necessarily have a causal relationship with

usage of a vaccine. The adverse event maybe an unfavourable or unintended

sign, abnormal laboratory finding, symptom or disease.

Several participants noted that the term “unfavourable” was not easily

translated, is a negative of a positive term and is not clear in its meaning.

Several participants raised the question of what is an “unfavourable or

unintended sign” compared to a sign. An abnormal laboratory finding,

symptom or disease was understood. Why was a sign dealt with differently?

Some participants proposed “an abnormal laboratory finding, symptom, sign or

disease”. One participant noted that the revised definition was more difficult to

explain at the working level compared to the previous definition. Participants

also argued that the term AEFI is too negative for the NIP and that they would

prefer a more neutral terminology, such as “vaccine safety surveillance”. Dr

Madhava Ram Balakrishnan said he would raise the concern about

“unfavourable” with the CIOMS.

Professor Noni MacDonald then discussed causality assessment: AEFI

case definitions and case scenarios (formerly Module G in the advance course)

followed by a new lecture on common fallacies and pitfalls (Module C) with

emphasis on anaphylaxis and sudden infant death syndrome (SIDS). The latter

was well received with many comments on pitfalls; more topics might be

included, such as misinterpretation of data, confusion with academic jargon,

etc. This was followed by Dr Ananda Amarasinghe’s presentation on the

systematic review of the vaccine safety database. This piqued the interest of

several participants and engendered good discussions.

3.2 Case studies

The participants worked on a case study (see Annex 4) through the WHO

revised causality assessment methodology. The approach to causality

assessment process for the case raised a number of issues, both clinical and

methodological. For example, the term “valid diagnosis” was found

confusing by some. Which diagnosis to choose – death, thrombocytopenia,

etc.? How should the different “diagnoses” be worked through – all on one


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form or several forms? Is the purpose of conducting AEFI causality

assessment solely to determine if the vaccine was associated with the

symptoms? Several noted that anxiety rose if only that is done as many then

ask why the child died. There may be a need to review what the parent

/media/politician is concerned about even if that is not a “medically

relevant diagnosis” upon review of the case. Queries were also raised about

some of the terminology on the WHO form as well as the process.

This was followed by a review of eight cases from the countries that had

been anonymized both to patient as well as to country and institutions (nine

AEFI cases were prepared for review, but due to time constraint, eight were

reviewed). Three working groups were carefully formed in order to contain

clinical expertise as well as a wide country mix. Out of the eight selected AEFI

reports reviewed in working group session, one case had onset in 2006, one in

2011, three in 2012, one in 2013 and two cases in 2014. The ages ranged

from one day to 18 months. The eight AEFI reports involved seven serious AEFI

cases with hospitalization; two cases recovered.

All groups worked enthusiastically with lively discussions and full

participation. The findings of the assessment were presented by the

representative of each working group. During the plenary discussions,

comments and insights made for lively audience participation.


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3.3 Format of the revised causality assessment methodology

More issues were raised about the format of the revised causality

assessment methodology and the applicability of some of the Brighton

definitions. The eight AEFI case histories and the salient features of

discussions are summarized in Annex 5. In several instances, participants

from other countries noted they had seen cases similar to the one

discussed. Many participants commented on how very helpful this session

was for not only increasing their knowledge about AEFI causality

assessment, but also on account of the breadth of the discussions and

different views of the cases in the groups. All saw this as a very valuable

exchange of experiences.

Given the comments about the WHO form and process for causality

assessment, a questionnaire was developed for the participants to specifically

comment on the usefulness of each section of the revised causality assessment

methodology and process (Annex 6). Out of 20 questionnaires distributed, 17

were returned by participants. Among the respondents, 82% felt that the

eligibility step was useful. However, 35% felt that some wording not always

easy to understand. Likewise, 82%, 71% and 82% indicated that the causality

question, event checklist and algorithm respectively were helpful. Only 18%

indicated that there were some situations where the event checklist did not

work, and 61% and 71% respectively expressed satisfaction at the approaches

used for the classification and summarizing the logic of classification.

Suggestions for making the methodology more user-friendly were made

by 35% of respondents. They included:

provision of more details on the indeterminate steps B1 and B2

particularly the differences;

addition of sections on feedback, recommendations and

corrective actions;

recommendations from the committee to prevent the event from

occurring in future; and

inclusion of an instruction page on how to fill the form, ensuring

that it covers the key definitions and terms used.


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Suggestions for improving causality assessment in the countries

included:

training for expert committee members, paediatricians or other

members;

training on critical cases of causality assessment through the

WHO collaborating centres, Brighton collaboration etc;

training on communication issues, especially in rumoured cases;

guidance on special considerations before immunization;

standardized verbal autopsy; and

special studies.

3.4 Vaccine safety and pharmacovigilance assessment tools

Dr Ananda Amarasinghe described vaccine safety and pharmacovigilance

assessment tools to review vaccine safety postmarketing surveillance

performance at the subnational levels. Many countries acknowledged a lack

of proper use of vaccine safety data for evidence-based practice and the

need to focus on improving critical reviews of database and vaccine safety

data analysis at different administrative levels. This session not only

generated much interest but also led to a number of questions. The

experience of using field data for analysis and interpretation in Sri Lanka


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provided an example of good practices for postmarketing surveillance of

vaccines.

3.5 Global vaccine pharmacovigilance initiatives

The different tools and resources available for vaccine pharmacovigilance

were demonstrated and the methods for accessing them were discussed by

Dr Madhav Ram Balakrishnan.

3.6 Vaccine adverse event information management System

Dr Ajit Pal Singh gave a brief overview of International Vaccine Institute in

Seoul, Korea and then reviewed the rationale for and how to use the

VAEIMS (Vaccine Adverse Event Information Management System). The

screen shot examples came from Sri Lanka which is piloting the programme

in the Region. This covered learning from the workshop, gaps, concerns

and potential solutions. The participants discussed the benefit of inviting

representatives of the vaccine industry in the intercountry workshop on

causality of AEFI, and felt that inviting industry might be helpful to enhance

understanding of AEFI issues. In Annex 7 an overview of the discussions are

provided. A key and strong recommendation was that such intercountry

workshops on causality assessment of AEFI take place in the Region every

12 to 28 months. The next discussion covered the potential for publication

of an article about this process (rationale, methods) with summary of the

eight cases and summary of recommendations from the meeting, that is,

more than just a meeting report. Permission to use the anonymized cases

will be sought and a title for the group volunteering to be on the writing

committee.

Recommendations and follow-up

(1) The major constraints of the national vaccine pharmacovigilance

are lack of planning for regular reviews of AEFI cases through a

committee of experts and the poor quality of investigation,

affecting data quality and causality assessments.


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(2) Countries are encouraged to advocate to the respective ministries

of health for additional resources to support the ongoing

functioning of the post-marketing vaccine safety surveillance and

to establish AEFI secretariat, particularly in vaccine-producing

countries.

(3) Guidelines to assist NIPs to plan for serious AEFI field

investigations and promptly respond to AEFI should be developed

(4) The WHO revised causality assessment methodology and CIOMS

AEFI definition should be reviewed based upon suggestions from

the homework questionnaire and concerns raised by end users at

the meeting. The questionnaire might be revised based on

responses for use in assessing causality using the WHO revised

causality assessment methodology in other settings.

(5) An informal technical working group should be set up to initiate

development of regional guidelines to plan serious AEFI field

investigation and to adapt WHO verbal autopsy to fit AEFI case

clinical needs.

(6) Several small-scale studies were identified to improve and

document signal detection; for example(1) to approach pediatric

societies in the Region to see if they could develop a practical set

of questions and observations for detection of infants with

clinically significant congenital heart disease for referral but not to

let this impede immunization; (2) to develop a small survey to

identify to what extent the NRA is involved in AEFI monitoring in

each of the participating countries in this forum and which

strategies countries have used to increase involvement; (3) to

explore development of a practical tool AEFI definition, time

interval, rates AEFI with different vaccines used in the Region and

(4) how immunization and AEFI can be better incorporated into

teaching at medical and nursing schools in the Region.

(7) A formal review of Brighton definitions should be undertaken to

develop definitions at levels that will work in settings where there

is no equipment and limited health worker training (for example,

outside a clinical trial in an LIC context)

(8) An article about the methods, findings, and recommendations

from the workshop should be prepared for publication.


15

Annex 1

List of participants

Bangladesh

Dr Shafiqur Rahman

Deputy Director and Programme Manager EPI

and Surveillance

EPI Headquarter

DGHS, Mohakhali,

Dhaka

Dr Md. Shafiqul Islam

Associate Professor

Department of Epidemiology

National Institute of Preventive and Social

Medicine (NIPSOM)

Mohakhali

Mr A A Salim Barami

Director (cc)

Directorate General of Drug Administration

and Deputy Chief, NCL

Dhaka

Bhutan

Mr Tshewang Dorji Tamang

Senior Programme Officer

Department of Public Health

Ministry of Health

Thimphu

India

Dr Ajay Khera

Deputy Commissioner (CH & I)

Ministry of Health & Family Welfare

New Delhi

Indonesia

Dr Hingky Hindra Irawan Satari

Head of National Committee of AEFI

National Committee of AEFI, Indonesia

Departemen IKA FKUI-RSCM

Jakarta Pusat

Dr Rahma Dewi Handari

Staff of Sub Directorate of Surveillance and

Risk Analyses of Therapeutic Products

Sub Directorate of Surveillance and Risk

Analysis of Therapeutic Product (PV unit)

National Agency of Drug and Food Control

Jakarta

Dr Sherli Karolina

Staff of Immunization Sub Directorate

Ministry of Health

Jakarta

Maldives

Ms Aishath Thimna Latheef

Public Health Programme Manager

Health Protection Agency

Ministry of Health

Malé

Nepal

Dr Neelam Adhikari

Chairperson, AEFI Committee Nepal

Consultant Pediatrician

B & B Hospital, Gwarku

Patan, Kathmandu

Dr Shyam Raj Upreti

EPI Chief,

Child Health Division,

Teku, Kathmandu

Sri Lanka

Dr Pathiraja Dissanayakelage Sriyani

Dissanayake

Deputy Director

Medical Technology & Supplies

(Cosmetic Devices & Drug Regulatory

Authority)

Colombo


16

Dr Duminda Samarasinghe

Consultant Paediatric Cardiologist

Lady Ridgeway Hospital for Children

Colombo

Thailand

Clinical Professor Dr. Suchitra Nimmanitya

Consultant

Department of Disease Control

Ministry of Public Health

Nonthaburi

Dr Pornsak Yoocharoen

Medical Officer, Senior Professional Level

Bureau of General Communicable Diseases



Nonthaburi

Miss Kanoktip Thiparat

Public Health Technical Officer – Professional

Level

Bureau of Epidemiology



Nonthaburi

Miss Pattreya Pokhagul

Pharmacist – Professional Level

Health Product Pharmacovigilance Center

Technical and Policy Administration Division

Food and Drug Administration


Nonthaburi

Timor-Leste

Mrs Liliana dos Santos Varela

Official VPD Surveillance

Department of Epidemiological Surveillance

Ministry of Health

Dili

Viet Nam

Dr. Nguyen Lien Huong

EPI Staff

National Expanded Programme on

Immunization (EPI)

National Institute of Hygiene and

Epidemiology

Hanoi

Dr Nguyen Thi My Hanh

Officer

Division of Vaccine, Biological and Biosafety

General Department of Preventive Medicine

Ministry of Health

Hanoi

WHO Headquarters, Geneva

Dr Madhav Balakrishnan

Medical Officer, Safety and Vigilance (SAV)

Regulation of Medicines and other Health

Technologies (RHT)

Department of Essential Medicines and

Health Products (EMP)

Health Systems and Innovation (HIS)

WHO South-East Asia Regional Office,

New Delhi, India

Mr Stephane Guichard

Regional Adviser

Vaccine Supply and Quality

Ms Aunyawan Thavinkaew

WHO Country Office, Thailand


Nonthaburi

WHO country offices

Dr Sujeet Kumar Jain

AEFI and VPD Surveillance Focal person

WHO Country Office for India – NPSP

New Delhi, India

Dr Santosh Gurung

New Vaccines Officer

Programme for Immunization Preventable

Diseases

WHO Country Office for Nepal

Kathmandu

Facilitators

Dr Ananda Amarasinghe

Consultant Epidemiologist

Epidemiology unit

Ministry of Health

Colombo, Sri Lanka


17

Professor Nora Noni Elisabeth Macdonald

Professor of Paediatrics

Dalhousie University

IWK Health Centre

Halifax, Nova Scotia

Canada

Observers

Mrs Teeranart Jivapaisarnpong

Director, Institute of Biological Products

Department of Medical Sciences


Nonthaburi, Thailand

Mrs Prapassorn Thanaphollert

Acting Director

Bureau of Drug Control




Mrs Porpit Varinsathien

Public Health Technical Officer

Bureau of General Communicable Disease




Dr Suchada JiamSiri

Medical Officer

EPI Programme

Bureau of General Communicable Diseases



Mr Pramote Akarapanon

Senior Pharmacist

Biological Products Section

Bureau of Drug Control




Ms Werayarmarst Jaroenkunathum

Chief of Vaccine Section

Institute of Biological Products

Department of Medical Sciences




18

Annex 2

Agenda

Sessions

1 Objectives

2 Country presentations: AEFI monitoring systems, past experience in investigation

and causality assessment

Bangladesh

Bhutan

India

Indonesia

Maldives

Nepal

Sri Lanka

Thailand

Timor-Leste

Viet Nam

3 Revised WHO Causality Assessment Methodology

4 Causality assessment: AEFI case definitions and case scenarios

5 Common fallacies and pitfalls

6 Systematic review of the vaccine safety database

7 Review of selected AEFI cases and categorization on a specially designed WHO

causality assessment form

8 Assessment tools to assess vaccine safety post marketing surveillance system

9 Global vaccine pharmacovigilance initiatives

10 International Vaccine Institute Vaccine Adverse Event Information Management

System

11 Building sustainable country and regional vaccine pharmacovigilance and

identification of needs and next steps

12 Closing remarks


19

An

nex 3

Su

mm

ary co

un

try p

ro

file, statu

s o

f A

EFI an

d p

erform

an

ces o

f vaccin

e p

harm

aco

vigilan

ce system

s

B

an

gla

desh

B

hu

tan

In

dia

In

do

nesia

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ald

ives

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al

Sri Lan

ka

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ail

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or-Leste

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t N

am

Co

un

try p

ro

file

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tal

po

p.

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7

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3

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0

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7

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3

17

4

2

11

4

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0

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Vaccin

e i

n t

he

imm

un

izatio

n

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ed

ule

BC

G,

DP

T-

Hep

B-H

ib,

OP

V,

MR

,

measle

s,

TT

BC

G,

Hep

B

(bir

th

do

se),

DP

T-H

ep

B-

Hib

MR

DP

T (

2 y

rs)

Td

HP

V (

12

yrs)

BC

G,

Hep

B,

DP

T-H

ep

B-

Hib

, O

PV

,

DT

P,

measle

s,

JE (

LA

V),

TT

Hep

B (

bir

th

do

se),

BC

G,

OP

V,

DP

T-

Hep

B-H

ib,

measle

s,

DT

,

Td

, T

T

BC

G,

OP

V,

DP

T-H

ep

B-

Hib

, m

easle

s,

MM

R,

TT

, D

T

BC

G,

DP

T-

Hep

B-H

ib,

OP

V,

MR

, JE

BC

G,

DP

T,

DP

T-H

ep

B-

Hib

, O

PV

MM

R,

JE,

Ru

bella,

DT

,

TT

BC

G,

Hep

B,

OP

V,

MM

R,

JE,

DT

P,

Td

,

DT

P-H

ep

B,

Influ

en

za (

po

p

at r

isk H

CW

)

BC

G,

OP

V,

DP

T-H

ep

B-

Hib

, m

easle

s,

TT

.

BC

G,

DP

T-

Hep

B-H

ib,

DP

T,

OP

V,

measle

s,

TT

,

ch

ole

ra (

2–5

yrs),

typ

ho

id

(3–5

yrs),

JE

(1–5

yrs)

Date n

ew

vaccin

e

intro

du

ced

-H

ep

B f

ro

m

20

03

to

20

05

-P

en

ta 2

00

9

-M

R 2

01

2

(Sep

t)

-m

easle

s 2

nd

do

se 2

01

2

Sep

t

Pen

ta 2

00

9

(Sep

t)

HP

V 2

01

0

(May)

Pen

ta (

started

20

11

in

2

states w

ith

grad

ual

exp

an

sio

n)

Td

(2

01

1)

Pen

ta (

20

13

)

in 4

/33

pro

vin

ces

20

14

all

pro

vin

ces

Pen

ta (

20

12

)

Pen

ta (

20

09

)

Pen

ta (

Jan

20

08

)

MM

R O

ct

20

12

JE L

AV

(Oct2

01

2)

NA

P

en

tavallen

t in

20

12

.

Pen

ta (

20

10

)

measle

s2

(20

11

)

DP

T b

oo

ster

(20

11

)

Co

verage f

or

each

an

tig

en

20

13

BC

G: 9

9%

OP

V3

: 9

2%

Pen

ta3

: 9

2%

measle

s: 8

6%

Fu

lly im

mu

ne:

81

%

20

12

BC

G: 9

4%

OP

V3

: 9

7%

DP

T-H

ep

B-

Hib

: 9

7%

MR

1: 9

5%

MR

2: 8

9%

20

13

BC

G: 9

2%

DP

T3

: 7

6%

Hep

B3

:6

7%

Hib

3: N

A

MC

V1

: 8

8%

MC

V2

: 4

2%

20

13

Hep

B0

:8

3.4

%

BC

G: 9

4%

DP

T-

Hep

B3

:9

5.6

%

OP

V4

: 9

5.3

%

MEA

: 9

3.5

%

20

13

BC

G: 9

9.7

%

DP

T3

: 9

9.4

%

Hep

B3

: 9

9.2

%

Hib

3: 9

9.5

%

MC

V1

: 9

9.4

%

MC

V2

: 9

8.6

%

20

13

BC

G: 9

7%

DP

T3

: 9

2%

Hep

B3

: 9

2%

Hib

3: 9

2%

OP

V3

: 9

2%

MC

V1

: 8

8%

20

12

Pen

ta3

: 9

9%

MM

R2

: 9

6%

JE: (

99

%)

20

13

BC

G: 1

00

%

DP

T3

: 9

9.4

%

OP

V3

:9

9.4

%

Hep

B3

:9

9.4

%

Measle

s:

98

.7%

JE3

: 8

9.3

%

20

13

BC

G: 8

1.6

%

Pen

ta3

: 7

6.3

%

OP

V3

: 7

6%

MEA

: 6

9%


20

B

an

gla

desh

B

hu

tan

In

dia

In

do

nesia

M

ald

ives

Nep

al

Sri Lan

ka

Th

ail

an

d

Tim

or-L

este

V

iet

Nam

Dates a

nd

no

.

vaccin

ated

SIA

an

d N

ID

s

in 2

01

2–2

01

3

if a

ny

20

th

NID

Jan

–Feb

20

12

: 4

4 0

93

25

5

21

st

NID

Dec 2

01

3:

20

6

30

0

62

No

v 2

01

2 R

ou

nd

1

(DT

P 2

–3

6 m

ths):

98

.3%

(DT

3–7

yrs):

10

0%

(Td

7–1

5 y

rs):

10

0%

Jun

20

13

Ro

un

d 2

(DP

T 2

–3

6m

s):

96

.6%

(D

T 3

–7

yrs):

97

.2

(Td

7–1

5 y

rs):

96

.3%

No

v 2

01

3 R

ou

nd

3

(DP

T 2

–3

6

mth

s):

97

.3%

(DT

3–7

yrs):

97

.6%

(Td

7–1

5 y

rs):

98

%

Vaccin

e

su

pp

ly

so

urces

Pro

cu

rem

en

t

servic

es a

greem

en

t

with

UN

ICEF,

Go

vern

men

t

fun

ded

. Lo

cal

ph

arm

aceu

tic

al

ind

ustr

y w

ith

cap

acity t

o

man

ufa

ctu

re

vaccin

es

Pro

cu

rem

en

t

servic

e

agreem

en

t

with

UN

ICEF.

Go

vern

men

t

fun

ded

Go

vern

men

t o

f In

dia

fro

m lo

cal p

ro

du

cers

mo

stly W

HO

PQ

All v

accin

e a

re

su

pp

lied

fro

m o

ne

do

mestic p

ro

du

cer

an

d a

re W

HO

PQ

UN

ICEF

Go

vern

men

t

of

Nep

al

excep

t P

VV

thro

ugh

UN

ICEF.

Vaccin

es a

re

all f

ro

m W

HO

PQ

so

urces.

Go

vern

men

t o

f

Sri-

Lan

ka f

ro

m

WH

O P

Q

so

urces.

On

ly

PV

V s

up

plied

by U

NIC

EF

with

GA

VI

fun

ds

Go

vern

men

t o

f

Th

ailan

d f

ro

m 3

local

man

ufa

ctu

rers

an

d im

po

rte

d

fro

m I

nd

ia,

Ind

on

esia

,

Ko

rea a

nd

Eu

ro

pe.

UN

ICEF

Go

vern

men

t

of

VT

N f

ro

m

local

su

pp

liers:

BC

G,

OP

V,

DP

T,

Hep

B,

JE,

oral

ch

ole

ra,

typ

ho

id,

measle

s a

nd

imp

orted

thro

ugh

UN

ICEF

Pen

tavale

nt

Statu

s A

EFI

Date A

EFI

co

mm

ittee

estab

lish

ed

10

Jan

uary 2

00

4

an

d lis

t u

pd

ate

d o

n

13

March

20

11

15

Ju

ly 2

00

9

Lis

t u

pd

ate

d

on

15

Ju

ne

20

12

25

Jan

uary 2

00

8 lis

t

up

dated

Ju

ly 2

01

3,

Secreta

ria

t o

f N

at’

l

AEFI

co

mm

itte

e

esta

blish

ed

in

20

12

.

30

Sep

tem

ber 1

99

7

an

d r

eo

rgan

ized

in

20

12

.

No

co

mm

itte

e

20

04

reo

rgan

ized

in

20

08

.

20

08

2

00

4 a

nd

up

dated

in

20

10

No

co

mm

itte

e


21

B

an

gla

desh

B

hu

tan

In

dia

In

do

nesia

M

ald

ives

Nep

al

Sri Lan

ka

Th

ail

an

d

Tim

or-

Leste

Vie

t N

am

List o

f A

EFI

co

mm

ittee

mem

bers

In

clu

des 1

3

mem

bers

rep

resen

tin

g, EP

I,

NR

A, p

ro

fesso

rs o

f

vir

olo

gy, p

ath

olo

gy,

paed

iatric

ian

s an

d

pro

fesso

rs o

f

med

ical co

lleges

Paed

iatric

ian

,

med

ical

sp

ecia

list,

mic

ro

bio

logis

t,

dis

tric

t h

ealth

offic

er, clin

ical

Lab

N

RA

an

d

ph

arm

acis

t

Ep

idem

iolo

gis

ts/p

ub

lic

health

sp

ecia

list,

paed

iatric

ian

, N

RA

,

mic

ro

bio

logis

t,

neu

ro

logis

t,

path

olo

gis

t, fo

ren

sic

scie

ntis

t, m

em

ber o

f

infectio

us d

iseases

su

rveilla

nce, p

ro

fesso

r

in teach

ing

ho

sp

ital/m

ed

ical

co

lleges

Rep

resen

tativ

e o

f

In

fectio

logis

t

In

do

nesia

P

aed

iatric

So

cie

ty (ID

AI),

In

do

nesia

n So

cie

ty o

f

Ob

stetric

s/G

yn

eco

logy

an

d H

ealth

Law

Asso

cia

tio

n

(P

ER

HU

KI);

paed

iatric

ian

s fro

m

th

e N

atio

nal P

ub

lic

Ho

sp

ital;

Fo

ren

sic

sp

ecia

list, EP

I

man

agers, N

RA

tech

nic

ian

s,

ph

arm

acis

ts,

rep

resen

tativ

e o

f th

e

legal b

ureau

M

OH

an

d p

ro

fesso

rs fro

m

med

ical in

stitu

tes.

NA

C

hair

ed

b

y

ind

ep

en

den

t

sen

ior

paed

iatric

ian

with

rep

resen

tativ

es

fro

m C

hild

Health

Div

isio

n,

Lo

gis

tic

s &

Man

agem

en

t

Div

isio

n,

Dep

artm

en

t o

f

Dru

g

Ad

min

istratio

n,

WH

O,

UN

IC

EF an

d

ped

iatric

ian

s

Pro

fesso

rs o

f

paed

iatric

s an

d

mic

ro

bio

logy

Facu

lty o

f

med

icin

es;

vir

olo

gis

ts,

path

olo

gis

ts,

imm

un

olo

gis

ts

Med

ical,

Research

In

stitu

tes, EP

I

man

agers, N

RA

rep

resen

tativ

es,

card

iolo

gis

t

Ch

ild

ren

Ho

sp

ital,

Neu

ro

logis

t

an

d p

ro

fesso

rs

of

ph

arm

aco

logy

an

d d

irecto

r o

f

Matern

al &

Ch

ild

H

ealth

div

isio

n

Ep

idem

iolo

gis

t,

paed

iatric

ian

fo

r

infectio

us

dis

eases,

paed

iatric

ian

fo

r

neu

ro

logy,

neo

nato

logy,

rep

resen

tativ

e

of th

e N

CL,

asso

cia

te

pro

fesso

r

fo

ren

sic

med

icin

e,

neu

ro

path

olo

gy,

ep

idem

iolo

gis

t

an

d

rep

resen

tativ

e

of th

e N

IP

NA

No

. o

f

co

mm

ittee

meetin

g

20

12

–2

01

3

Irregu

lar

20

12

: 2

20

13

: 3

Estab

lish

ed

fix

ed

cale

nd

ar, m

et fo

ur

tim

es b

tw

A

ugu

st

20

13

to

M

arch

2

01

4

Co

re m

eetin

g tw

ice a

year +

u

po

n req

uest.

AEFI co

mm

ittee m

et

10

tim

es in

2

01

2 an

d

4 tim

es in

2

01

3 to

co

nd

uct cau

sality

assessm

en

ts

NA

20

12

: 3

20

13

: 1

20

12

: 4

20

13

:3

NA

AEFI

gu

id

elin

e

dates an

d

up

date

Gu

idelin

es (2

00

5)

revis

ed

in

2

01

0 an

d

SO

P d

evelo

ped

in

20

11

.

Gu

idelin

e (2

00

5),

AEFI tech

nic

al

gu

idelin

e (2

01

2); A

EFI

MO

H regu

latio

n

(2

01

3)

Natio

nal

gu

idelin

es

un

der

develo

pm

en

t

Gu

idelin

es

20

03

in

Nep

ale

se

lan

gu

age in

20

08

Gu

idelin

es

20

07

u

pd

ated

in 2

01

2

20

03

an

d

up

dated

in

20

08

NA

2

00

3 an

d

up

dated

in

20

13

an

d

20

14


22

B

an

gla

desh

B

hu

tan

In

dia

In

do

nesia

M

ald

ives

Nep

al

Sri Lan

ka

Th

ail

an

d

Tim

or-

Leste

Vie

t N

am

Defin

itio

n

to

id

en

tify

serio

us

AEFI, i.e.

wh

at is

rep

orted

as

serio

us A

EFI

Death

,

ho

sp

italizatio

n,

clu

ster o

f rep

ortab

le

AEFI,

paren

tal/co

mm

un

ity

co

ncern

s

In

clu

des d

eath

,

ho

sp

italizatio

n,

clu

ster, p

ersis

ten

t o

r

sig

nific

an

t d

isab

ility

/in

cap

acity o

r life-

th

reaten

ing co

nd

itio

n

Severe lo

cal

reactio

n,

inje

ctio

n site

ab

scess

BC

G

lym

ph

ad

en

itis

Hig

h fever

(m

ore th

an

1

01

F) w

ith

in 4

8

hrs

Rash

Seiz

ures w

ith

in

14

d

ays

En

cep

halitis

/

Men

ingitis

with

in 2

8 d

ays

En

cep

halo

path

y

with

in 3

d

ays

Lo

ss o

f

co

nscio

usn

ess /

sh

ock w

ith

in 4

8

ho

urs

An

ap

hyla

xis

To

xic

sh

ock

syn

dro

me

VA

PP

Ho

sp

italizatio

n

Death

Pu

blic co

ncern

s

Death

s an

d

ho

sp

italizatio

n

Death

s,

ho

sp

italizatio

n,

an

y even

t

believed

to

b

e

asso

cia

ted

to

vaccin

e an

d/o

r

an

y p

eo

ple

co

ncern

s

Death

,

ho

sp

italizatio

n

an

d cases

su

sp

ected

to

b

e

asso

cia

ted

to

vaccin

e, p

eo

ple

co

ncern

s

NA

A

nap

hyla

ctic

sh

ock,

into

xic

atio

n

sh

ock

syn

dro

me,

su

sp

ected

pro

gram

me

erro

r an

d

death


23

B

an

gla

desh

B

hu

tan

In

dia

In

do

nesia

M

ald

ives

Nep

al

Sri Lan

ka

Th

ail

an

d

Tim

or-

Leste

Vie

t N

am

Vaccin

e P

V p

erfo

rm

an

ce

No

. o

f

rep

orted

AEFI cases

20

12

–2

01

3

22

98

(2

01

2)

22

88

(2

01

3)

3 (2

01

2)

16

(2

01

3)

38

6 (2

01

2)

53

6 (2

01

3)

On

ly serio

us cases are

rep

orted

to

co

mm

ittee. N

on

-

serio

us cases rep

orted

th

ro

H

MIS, b

ut d

ata

no

t availab

le at

natio

nal le

vel yet.

10

4

69

(2

01

2)

18

6

21

(2

01

3)

1

9 (2

01

2)

22

(2

01

3)

64

55

(2

01

2)

13

59

(2

01

2)

76

9 (2

01

3)

0 (2

01

2)

1 (2

01

3)

30

(2

01

2)

31

(2

01

3)

No

. o

f

serio

us A

EFI

rep

orted

20

12

–2

01

3

54

(2

01

2)

73

(2

01

3)

1 (2

01

2)

3 (2

01

3)

38

6 (2

01

2)

53

6 (2

01

3)

12

3 (2

01

2)

12

0 (2

01

3)

1

9 (2

01

2)

22

(2

01

3)

24

14

(2

01

2)

89

4 (2

01

3)

15

4 (2

01

2)

83

(2

01

3)

0 (2

01

2)

1 (2

01

3)

30

(2

01

2)

31

(2

01

3)

No

. o

f cases

in

vestigated

54

(2

01

2)

62

(2

01

3)

1 (2

01

2)

3 (2

01

3)

32

% o

f cases h

ad

tim

ely

in

vestig

atio

n

with

Fir

st In

vestig

atio

n

Rep

ort availab

le

(2

01

2)

30

% (2

01

3)

16

3 (2

01

2)

15

6 (2

01

3)

No

A

EFI

investig

ated

19

(2

01

2)

22

(2

01

3)

24

14

(2

01

2)

89

4 (2

01

3)

11

07

(2

01

2)

46

9 (2

01

3)

0 (2

01

2)

0 (2

01

3)

30

(2

01

2)

31

(2

01

3)

No

. o

f cases

review

ed

b

y

co

mm

ittee

15

(2

01

2)

17

(2

01

3)

1 (2

01

2)

3 (2

01

3)

86

(2

01

2) in

clu

des

backlo

g p

revio

us

years

89

(2

01

3)

16

3 (2

01

2)

15

6 (2

01

3)

1

9 (2

01

2)

22

(2

01

3)

8 (2

01

2)

2 (2

01

3)

11

07

(2

01

2)

46

9 (2

01

3)

NA

A

ll


24

Annex 4

Case Study

AEFI investigation report

TM, the daughter of XX and YY, residing at 66 C K Colony, Green Park,

Salem City 1203, was born on 1 October 2010. She was born by lower

segment Caesarean section at the Salem general hospital at a gestational

age of 38 weeks+2 days. Her birth weight was 3200g. Apgar score at birth

was 10. There were no significant findings detected during neonatal

examination.

She received measles vaccine at 11:30 on 4 September 2011 along

with Vitamin A (100 000 IU batch no. SA 298 expiry date March 2012) at

the Pushpa clinic in C.K colony. There was no postimmunization

observation for AEFI. The measles vaccine (Khasravac) batch number was

605434. The expiry date was 12 December 2014. The diluent (batch no

A3D4345 expiry date Jan 2015) recommended by the manufacturer was

used. The vaccine (0.5 ml) was given by the subcutaneous route in the left

upper arm. The needle length and gauge was 25 mm, 23G. Thirty children

were immunized at the same clinic on the same day and nine children

were immunized with the same vaccine vial at the same clinic on the same

day. There were no similar events with other children.

There was no breakdown in the cold chain since the receipt of

incriminated stocks of vaccine at the provincial office was correct according

to the daily temperature record. There was no breakdown in the cold chain

since the receipt of incriminated stocks of vaccine at the distribution point

was correct according to the temperature data logger and the status of the

VVM on the stocks of incriminated vaccines was normal (stage 1). The clinic

was recording vaccine reconstitution time on the vial labels.

On the evening of the day of immunization the mother noticed that

TM had mild fever. On 7 September the mother noticed that she had high

fever, cough, vomiting and flushed face. On 12 September, she was

admitted to the General Hospital, Salem with a tentative diagnosis of lower

respiratory tract infection. She was treated with panadol, piriton,

cefaloxine, salbutamol, theophylline and diclofenac sodium suppository


25

(12.5 mg). On admission, the white blood cell (WBC) count was 3800

mm−3

and platelet count, 152 000 mm−3

.

On the morning of 13 September, she had high fever and right

hypochondrial tenderness. Liver was 1 cm, tender. She was

haemodynamically stable. The WBC count was 1300 mm−3

and the platelet

count, 112 000 mm−3

(05:00). She was provisionally diagnosed with a

probable dengue infection. That afternoon, she developed watery

diarrhoea and convulsions and was treated for acute gastroenteritis with

intravenous (IV) antibiotics and fluids. The evening platelet count was

77 000 mm−3

(17:00) and 54 000 mm−3

(20:00).

During the 21:00 evaluation on 13 September, she was considered to

have entered into critical phase with haemodynamic instability (heart rate

>200, systolic blood pressure 60 mmHg). Patient on intravenous fluids over

six hours exceeding the fluid quota (1330 ml given – 90.5%). She was

transferred to the intensive care unit (ICU). The HR remained high –

haemodynamically unstable. Pupils wide, tachypnoea, peripheral cyanosis

– fluid overload. She died at 09:00 on 14 September.

TM’s father is working as an agricultural labourer in Salem. According

to the field staff, there are some conflicts between mother and father. There

are no siblings. Prior to immunization, TM's feeding was normal and she

had normal activity. Her growth and milestones were normal. She did not

have any obvious allergies to any particular food. There is no evidence of

abuse/ harm/ neglect/ accidental injury/previous need for child protection.

There was history of febrile illness a week prior to vaccination, but at the

time of immunization, she was fine. She did not receive any medication

within 24 hours prior to immunization. She had received BCG, pentavalent

vaccine (three doses) and oral polio vaccine (OPV) earlier. The documents

are unavailable.

An autopsy was conducted and the official report is awaited. The

forensic pathologist indicated that the appearance is compatible with a viral

infection. There was, however, no macroscopic evidence of bleeding or

fluid leakage. The relevant specimens were collected and sent for

laboratory analysis.


26

Annex 5

Eight AEFI case reports with findings of working group

and summary of plenary discussions

Group 1 – Case 1

Sex: Male

Date of birth: 2 March 2012

Address: Rural

A. Information about the case

Variables Investigation findings

1 Age at the day of

vaccination

6 weeks and 6 days

2 Birth date 2 March 2012

3 Date/time that received

vaccine

19 April 2012 at 11:00

4 Type of vaccine DPT-HepB-Hib first dose and OPV first dose

5 Place of vaccination Routine immunization session

6 Date/time of onset of AEFI 19 April 2012 at 13:30

7 Date/time of death 20 April at 20:00

8 Health history Four days prior to vaccination, the child attended clinic

in a health post and received treatment with cefixime

oral suspension and cetamol for cough, cold, nose block

and fever.

Born in rural hospital 30 km away from residence. The

pregnancy and delivery was uneventful. The parents are

both 20 years old and have been married for the past

three years and this was their first child. Weight of the

baby at birth was 3.5 Kg. The baby was exclusively

breastfed and doing well.


27


9 Symptoms and treatment Field investigation was conducted by local health

authorities.

On 19 April 2012 at 11:00, a 48 days old baby

weighing 4.5 kg received DPT-HepB-Hib first dose and

OPV first dose. About 15 minutes later, on his way back

home, the child became blue and developed

convulsions.

Baby was brought to hospital and was treated with:

O2 inhalation (O

2 saturation increased from 44% to

76%), IV fluids, injection phenobarbitone, IV cefotaxim

and cloxacillin.

However, O2 saturation broke down, and the child was

referred to another hospital three hours away, but on

arrival, the equipment was not available and the child

was brought to a third hospital admitted in ICU at

around midnight on 19 April.

In the hospital, the child was ventilated and given

antibiotics, fluids and other related investigations.

On 20 April 2012 the child died at around 20:00.

10 Condition of other children

vaccinated in the same

health facility

It was not possible to visit the health facility because in

the rural area vaccination sessions take place once a

month. However, stock records in the district vaccine

cold room showed 6625 doses of the same lot of

pentavalent vaccine had been distributed and no other

case of AEFI was reported.

11 Vaccine management The cold chain was maintained in good order at the

vaccination centre and districts. Small quantities of

vaccine are distributed to health centres because power

supply was not reliable at the primary health care level.

12 Details of implicated

vaccine/ diluent

administered

DPT-HepB-Hib Lot Number 1422120 manufactured by

Berna Biotech Korea.

13 Laboratory/autopsy Brain – congested; both lungs – congested and

oedematous with fluid in pleural cavity; heart – normal;

abdominal cavity contains fluid; liver – elongated and

congested; spleen –elongated; intestine – congested;

spleen full of fluid; both kidneys – normal. Cause of

death autopsy: septicaemia.


28


14 Investigation team’s

conclusion

Septicaemia with multiple-organ failure. Coincidental

AEFI as the baby had pre-existing on-going pneumonia

leading to septicaemia.

B. Working Group 1 – Case 1: findings and conclusions

In Step 1 of the revised causality assessment methodology for causal

association, the valid diagnostic identified by the group is anaphylaxis. Then

the case definition as per Brighton definition is summarized in the box. The

question for causality is “Has the pentavalent DPT-HepB-Hib vaccine

caused the anaphylaxis?”

To question I, “Is there strong evidence for other causes?” the group

responded “Yes” because the autopsy findings showed septicaemia with

multi-organ failure.

To question II, “Is there a known causal association with the vaccine

or vaccination?”, the group responded “Yes” because evidence in the

literature that the vaccine may cause anaphylaxis in about 20 individuals

per million doses administered. Rapid progression within 20 min but the

group did not know if there is a specific test to demonstrate the causal role

of the vaccine. All the other questions responses were negative.

To question III “Is there a strong evidence against a causal

association?”, the group responded “Yes”.

To question IV, “Other qualifying factors”, the group responded “Yes”

to the two questions “Could the event occur independently of

vaccination?” and “Could the event be a manifestation of another health

condition?” because for the first question, anaphylaxis can occur due to

many other causes and for the second question because of the pre-existing

illness of the child at the time of the vaccination. In responding to the

questions, the group identified exposure to potential risk factors or toxin

because the child had fever-four days prior that could reveal an acute

illness prior to the event. The group also acknowledged that the patient was

under antibiotics and antipyretics prior to the vaccination. The group

identified a biological plausibility that the vaccine could cause the event.


29

The conclusion of the group that the available evidence could

conclude that the classification is coincidental association with the

vaccination because the child had pre-existing illness prior to the

vaccination and autopsy findings showed septicaemia and multiorgan

failure.

During plenary discussions, Professor Noni Macdonald suggested that

we could also conclude that there is no evidence of toxic shock as well as

no evidence of hypotonic hypo-responsive episode (HHE) because HHE

does not cause death. The audience also mentioned that there are

programmatic issues to be addressed including proper examination before

vaccination, for example, taking the pulse. Case management in the

hospital also should be reviewed. Overall, the audience enjoyed the value

of the exercise. It is anonymous, allowing to make recommendations away

from conflict of interest issues. There are communication challenges to

communicate such an event to the family and the public at large.


30

Group 1 – Case 2

Sex: no data

Date of birth: 19 November 2013

Address: Rural

A. Information about the case:


1 Age at the day of

vaccination

One year and six weeks

2 Birth date 19 November 2013


vaccine

31 December 2013, no time provided

4 Type of vaccine DPT-HepB-Hib (right thigh)

OPV (oral)

5 Place of vaccination Rural

6 Date/time of onset of AEFI 3 January 2014 11:30 (notification time)

7 Date/time of death Recovered

8 Health history The child had a history of cough two days prior to

vaccination.

The child had received BCG, Hep B and OPV as per

immunization schedule.

9 Symptoms and treatment The child was diagnosed with bronchiolitis/anaemia. He

received injections of ampicillin and gentamicin and

dexamethasone.



health facility

No data

11 Vaccine management No data

12 Investigation of vaccine No data

13 Autopsy Not performed


conclusion

Inconsistent causal association to immunization because

the child was sick prior to the immunization.


31


The valid diagnostic used by the group was “Has the pentavalent caused

bronchiolitis?” To question I, “Is there strong evidence for other causes?”,

the group responded “Yes” as anaemia was suggested in the history of the

patient. All the questions in parts 2 and 3 were responded to by negatives.

In part IV “Other qualifying factors for classification”, the group

responded “Yes” to the question “Could the event occur independently of

vaccination…?” because bronchiolitis is common in this age group in many

low and middle-income countries (LMICs). The factor that informed the

group about potential exposure to toxin or risks of disease prior to

vaccination is that the child was reported to cough for two days before the

vaccination.

The group concluded that the causal association with the vaccine is

indeterminate due to lack of information regarding laboratory

investigations, clinical history and detailed course of events.

During the plenary discussion, participants asked the difference

between indeterminate and unclassified. Professor Noni MacDonald

explained that indeterminate refers to an association that is possible, but

one element does not match the case definition, for example, timing is not

correct. Unclassified means that we do not have enough information.


32

Group 1 – Case 3

Sex: Male


Address: Rural



1 Age at the day of

vaccination

1 year and 6 months



vaccine

21 September 2006. Time of vaccination not recorded

4 Type of vaccine DTP4 (left hip) Lot No 000444 Expiry October 2006

JE (upper arm) Lot No JJ4806-3 Expiry February 2007

OPV4 (oral) Lot No Z5316 Expiry October 2006

5 Place of vaccination District hospital

6 Date/time of onset of AEFI 22 September 2006, fever and difficulty in walking

26 September 2006, could not walk, ptotic right eye lid,

drowsy, cannot drink milk. He was then referred to

another hospital.

7 Date/ time of death Recovered

8 Health history 20 March 2005, born in hospital

3 September 2005, dyspepsia

4 February 2006, acute upper respiratory infection,

unspecified

9 June 2006, acute upper respiratory infection,

unspecified

9 Symptoms and treatment 22 September 2006, hardness on the left hip was

treated by the mother with lemon and massage of the

area which turned to a bruise. Mother noticed that the

child started limping in the morning, and in the evening

didn’t want to walk, arms still can move, no fever,

regular urine. The mother took the child to community

hospital and was prescribed with prednisolone (5mg/ta)

1x1 @pc


33


The child developed fever and could not walk. Brought

to the community hospital, he was diagnosed with

myalgia and asked to come back in a week to follow up.

On 26 September 2006, the child came before the

appointment because his legs were very weak and

couldn’t walk, ptotic right eye lid, drowsy, cannot drink

milk. The doctor transferred him to the district hospital.

At first the child couldn’t breathe by himself; he had to

be put on a machine to help him breathe.

The medical record is as below:

The patient was very weak, no strength, refused to sit

down, didn’t walk, started to have drooping eye lids so

the mother took him to community hospital and found

that V/s: BT 36.8c BR 120, PR 36, ptosis RE, pupil 3 mm

RTL BE, Motor upper gr V. lower gr O-I, DTR 1 + all,

BBK absent, Clonus neg Imp. Paraplegia so the patient

was sent to the main hospital.

PE: BW 9.1 kg

V/S: BT 37.3, PR 184, RR36, BP 90/60

HEENT: not pale, no jaundice, no cervical

lymphadenopathy

Heart: normal S1, S2, no murmur

Lung: clear

Abd: soft, not tender, liver and spleen cannot be

palpated

Ext: no petechiae, no oedema

N/S: MSE: good consciousness

CN: pupil 3 mm RTL BE, ptosis RE – 50%

EOM by observed – 30-40% all direction,

No facial palsy; gag reflex: positive

Sensory can’t be evaluated

Motor flaccid tone, Power: UE gr III, LE gr 0

DTR: upper1+, lower 0

BBK absent, Clonus: neg, Stiffness of neck: neg

Investigation:

CT brain: 26 September 2006: Normal study

4 October 2006: Mild cerebral atrophy causing dilate

ventricular system Otherwise normal

Electrodiagnostic findings (NCV):

Small CMAP amplitude, normal motor distal

latency and motor NCV of Rt: median, ulnar and


34


peroneal nerves

No CMAP response of RT tibial nerve

No SNAP response of Rt sural nerve

Normal repetitive nerve stimulation

Axonal loss, motor greater than sensory polyneuropathy

DD: acute inflammatory demyelinating

polyradiculoneuropathy acute axonal form (acute

axonal Guillain–Barré syndrome (GBS))

LP (26 September 2006) – colourless, no cell, CSF

protein 51 CSF sugar 72 BS

CSF IgM (12 October 2006): Herpes Simplex Virus IgM

– Negative

Dengue IgG Positive

JE IgM to follow

Enterovirus to follow

Other: CBC (2 September 2006) : Hb 12.2, Hct 3,

WBC 6880 (N50, L43, M6, Eo1) Plt 664 000 BUN 13,

Cr 0.1 Electrolyte: Na 140, K 4.4, Cl 98, CO 220

Progress note:

28 September 2006: Weaker, drowsier

PE: MSE: drowsiness

CN: ptosis BE, total ophthalmoplegia, drooling, facial

BE, gag reflex: neg

Motor gr 0 all DTR O all

Rx: Intubation and ventilator support

Start IVIG but need to wait for medicine from

Bangkok

IVIG 400 mg/kg per day × 5 days

4 October 2006: High fever V/S: unstable

IMP: Sepsis with septic shock and pneumonia

Rx:- Start antibiotic: Tienam + inotropic drug

Septic work up: H/C: pneumonia

5 October 2006: clinical starts to be stable N/S: eye

opening, eye blinks. Eye EOM 10-20% Motor: gr 0 all

DTR 0

22 October 2006 Before D/C N/S: MSE: good

https://www.google.ca/url?q=http://emedicine.medscape.com/article/1169959-overview&sa=U&ei=TDNqU_CTPOLWyQH19oDIDg&ved=0CB8QFjAA&usg=AFQjCNESa3ioSiOs-tKZEwVvZd8kF7Braw

https://www.google.ca/url?q=http://emedicine.medscape.com/article/1169959-overview&sa=U&ei=TDNqU_CTPOLWyQH19oDIDg&ved=0CB8QFjAA&usg=AFQjCNESa3ioSiOs-tKZEwVvZd8kF7Braw


35


consciousness

CN: intact motor: UE gr IV, LE gr III DTR:0



health facility

The other 18 children who got vaccine at the health

station on the same day, as the patients have no unusual

symptoms.

Children who received the same type and lot number of

vaccine include: DTP 1174 people, OPV 1462 people,

JE 387 people. All has no unusual symptoms.

11 Vaccine management Vaccine DTP lot number 000444 expiry October 2006,

manufacturer P.T. Bio FARMA

Vaccine OPV lot number Z5316 expiry February 2007,

manufacturer Aventis Pasteur in France

Vaccine JE lot number JJ4806-3 expiry 6 October 2006,

GPO

By reviewing details and quality control policies from

summary protocol and quality control for vaccines, it

was found that all vaccines were produced and quality

controlled according to the factories’ standards. So it

could be confirmed that the vaccines passed the safety

standard.

12 Investigation of vaccine Vaccine DTP lot number 000444 expiry October 2006,

manufacturer P.T. Bio FARMA

Vaccine OPV lot number Z5316 expiry February 2007,

manufacturer Aventis Pasteur in France

Vaccine JE lot number JJ4806-3 expiry 6 October 2006,

GPO

By reviewing details and quality control policies from

summary protocol and quality control for vaccines, it

was found that all vaccines were produced and quality

controlled according to the factories’ standards. So it

could be confirmed that the vaccines passed the safety

standard.

Investigation of vaccine DTP lot number 000444 expiry

October 2006, produce company P.T. BIO FARMA

Appearance – Pass

sterility test – Pass

Abnormal toxicity test – Pass

Specific toxicity for diphtheria and tetanus component –


36


Pass

Specific toxicity for whole cell pertussis – Pass

Conclusion: Vaccine is at the standard as agreed by

manufacturer and not below the standards set by WHO

Investigation of vaccine OPV lot number Z5316 expiry

February 2007 from Aventis Pasteur, France

Appearance – Pass

Sterility test – Pass


Hydrogen ion – Pass

Protein content – Pass

Identity test – Pass

Bacteria endotoxin test – Pass (this is an additional test,

not used in standard of vaccine investigation; if

compared to other type of vaccine ex Hep B, amount of

endotoxin is at the normal standard level)

Conclusion: Vaccine meets the required standard

Investigation of vaccine JE lot number JJ4806-3 expiry 6

October 2006 produced by GPO

Appearance – Pass

Sterility test – Pass`


Protein content – Pass

Inactivation – Pass

Pyrogen – Pass

Bacterial endotoxin test – Pass (this is an additional test,

not used in standard of vaccine investigation; if

compared to other type of vaccine ex Hep B, amount of

endotoxin is at the normal standard level)

13 Laboratory/autopsy Specimen Date Laboratory

location

Results

CSF for

Virus

24 October

2006

Department

of Medical

Sciences,

MOPH

Herpes simplex

virus IgM –

negative

Dengue IgG –

positive

JE IgM – waiting

for a result

Enterovirus –

negative


37


CSF 12 October

2006

Regional

hospital

Protein 114,

glucose 68

Stool for

polio

12 October

2006

Department

of Medical

Sciences,

MOPH

Negative

Blood

culture

4 October

2006

Regional

hospital

Microbial

susceptibility =

Acinetobacter

sp., K.

pneumoniae +

ve

CT brain 4 October

2006

Regional

hospital

Mild cerebral

atrophy causing

dilated

ventricular

system


conclusion

Elementary diagnosis paraplegia r/o GBS from vaccine

was given from the hospital on 24 October 2006

Last diagnosis encephalopathy neuropathy r/o (GBS)

post vaccination

B. Working group 1 – Case 3: Findings and conclusions

The valid diagnostic used by the group was “has the DTP4 caused GBS”.

The group then compared GBS case definition levels 1 to 6 (Brighton

definitions) with the clinical examination and laboratory investigations

available in the investigation report. In the absence of other clinical

examination and laboratory tests that could confirm other cause and with

the documented evidence of risks of GBS following DTP vaccination, the

group concluded there is consistent causal association of this event with

immunization because GBS is known to be associated with DTP.

Professor Noni MacDonald agreed with the group, although she

mentioned that GBS is not well documented in very young children in

relation to vaccines but is known to occur following campylobacter

infection (not tested for). GBS is a very rare event and sometimes has no

known cause It is likely that it would have been helpful to discuss the

possibility of vaccine-associated paralytic poliomyelitis.


38

Group 2 – Case 1

Sex: Male


Address: Rural



1 Age at the day of vaccination One week and six days



vaccine

6 January 2014. Time not specified

4 Type of vaccine DTP-HepB-Hib

OPV

5 Place of vaccination Not specified

6 Date/time of onset of AEFI 6 January 20:00

7 Date/time of death 7 January 2014 at 11:00

8 Health history Child reported well before the vaccination. He attended

three postnatal clinics.

9 Symptom and treatment January 6 2014, the baby was immunized and returned

home.

January 6 at 18:00 the baby had mild fever and mother

gives syrup paracetamol.

At 20:00 baby was crying excessively and not feeding.

At 21:30 the baby had three episodes of loose stools but

no vomiting.

January 7 at 00:00 (midnight), the baby was found

lethargic and taken to the emergency unit of the national

referral hospital.

January 7, the child was admitted in the hospital in shock

and had cyanosis, hypotension, hypothermia, anaemia and

severe respiratory distress with grunting. He received IV

fluids, O2 inhalation, Inj. ceftriaxone, Inj. gentamicin,

ranitidine. The baby’s condition deteriorated and he

developed UGI bleed including bleeding from the

endotracheal tube.

At 10:40 the baby suffered a cardiac arrest.

January 7, at 11:00 the baby was declared dead.


39


vaccinated in the same health

facility

No data


12 Investigation of vaccine No data

13 Laboratory/autopsy Blood culture test results not available.

Complete blood count (WBC, 21.8 × 10³; neutrophils,

64%; lymphocytes, 29%; Hb, 7.3g/dl; ESR 7; CRP, 4.1),

LFT-ALP, 460; total bilirubin, 2.2; direct bilirubin, 0.9;

sodium, 129; potassium, 5.9; chloride, 101.


conclusion

Anaphylaxis/sepsis


The valid diagnostic used by the group who reviewed this case was septic

shock but the group noted the absence of a Brighton case definition for

this. The causality question is “Does the DTP-HepB-Hib and OPV caused

sepsis?”

To question I “Is there strong evidence for other causes?”, the group

responded “Yes” because clinical exam show multiorgan dysfunction and

the laboratory tests reveal leukocytosis.

To question II “Is there a known causal association with the vaccine?”,

the group responded “Yes” because anaphylaxis may be caused by vaccine.

All the other questions were answered “unknown” because of lack of

information in the investigation report. However, the outcome of the group

discussion was that this event was not caused by excessive anxiety and the

elapsed time too long for sepsis or anaphylaxis. It was also agreed that OPV

could be taken out of consideration, because although it could cause sepsis,

the question would be in what way.

The participants recognized that the event could happen

independently of vaccination, given the underlining illness of the baby. The

consensus was the case is coincidental because the baby showed signs of

sepsis and developed shock 12 hours after immunization. There was

evidence of bacterial infection in the form of leukocytosis and diarrhoea

episodes and liver dysfunction.


40

Professor Noni Macdonald mentioned that there are in fact two

questions to answer with the first question being did the vaccine cause the

event and the second being did the vaccine contribute to the event which

is more difficult to answer in the absence of in-depth clinical and post-

mortem investigations. In this connection, the group acknowledged the

difficulties in proceeding with post-mortem autopsy and a verbal autopsy

adapted to AEFI and countries with limited resources could improve

investigation and thus data quality.


41

Group 2 – Case 2

Sex: Male

Date of birth: 11 February 2013

Address: Rural



1 Age at the day of

vaccination

52 days

2 Birth date 11 February 2013


vaccine

03 April 2013 at 12.00

4 Type of vaccine DTP-HepB-Hib dose 1, batch 124P2011B

OPV dose 1, Batch 2010312

5 Place of vaccination Health post

6 Date/time of onset of AEFI 3 April 2013 at 13:00

7 Date/time of death 4 April 2013 at 15:30

8 Health history History of vomiting after feeding since birth. Other than

that the child was asymptomatic and was playful and

feeding well until the vaccination. The birth history was

uneventful, with a normal vaginal delivery in zonal

hospital. BCG was given at birth.

09 Symptom and treatment According to the mother, the child was well prior to

receiving the vaccine. The Penta /OPV 1 was

administered on 3 April 2013 at 12:00 (most probably).

They left for home 5–10 minutes later and reached

home in about 25 minutes. The baby slept for about 15

minutes. The child woke up and had a vacant look,

crying and had difficulty in breathing (around 13:00) -

bluish coloration was also present. The mother tried to

breastfed but the baby did not respond well. The child

was rushed to the private clinic, where no treatment/

intervention done. After the child’s condition

deteriorated, he was taken to the health facility and

with any further treatment was referred to the GYT

Medical College and was admitted at about 19:30. The


42


child was attended at 19:45 at the GYT Medical

College with C/C;

Sudden onset of abdominal distension about six hrs

Rapid breathing with difficulty with chest in drawing

and marked shortness of breath about six hrs

On examination severe respiratory distress; crepilations

and rhonci bilaterally.

The treatment the child received included: NG

decompression; Inj. ceftriaxone 150 mg IV BD, Inj.

amikacin 35 mg IV BD, Inj. Isolytep 175 ml IV 12

hourly Inj. Lasix 3.5 mg IV OP.

Call was attended at ICU at 11.15 on 4 April 2013 with

nil respiratory effort and cyanosis, CPR done and Inj.

adrenaline 1ml IV and Inj. aminophylline was also

given and endotracheal intubation was done, shifted to

NICU under ventilator support. Initially was in SIMV

mode in ventilator was switched at CPAP Mode as the

saturation was varying from 70-75% and fighting.

Hypotension was also stated in the h/o. On 4 April

2013, at 15.15, call attended with no signs of life

observed and was declared dead at 15:30.



health facility

Six other children were vaccinated at the outreach

clinic on 3 April 2013. The vaccinator had vaccinated

the first three children with the remaining vial from the

previous day (MDVP – multi dose vial policy and ten

dose DPT vial available). Three other children were

vaccinated with the newly opened vial; the AEFI

notified child was the last child to be vaccinated with

the newly opened vial.

The other children were also investigated to see if any

concurrent cases. Another child was observed with

symptoms of upper respiratory tract infection was

referred to the hospital for observation, was discharged

the following day

11 Vaccine management Maintenance of the cold chain was satisfactory

12 Investigation of vaccine No investigation on the vaccine. VVM status not

recorded

13 Laboratory investigation Findings:

GC: ill looking having marked intercostal respiratory

system indrawing and abdominal distension.


43


RR: 88/min with marked intercostal and sub costal

indrawing.

Temp: 98 Fahrenheit.

SPO2: 89% without O

2

Chest: coarse basal b/l creps + and expiratory grunting

Investigations:

Hb, 10.2; TC, 28 500; N, 84%; L 82%; E, 3%; N, 1%


conclusion

Pneumonia with severe illness with septicaemia

B. Working group 2 – Case 2: findings and conclusions

The group identified “pneumonia” as the valid diagnosis and thus created

the causality question “Has the Penta1 and OPV1 vaccines/vaccination

caused pneumonia?” To question 1, is there strong evidence for other

causes, the group responded “Yes” because symptoms of acute respiratory

distress, abdominal distension, cyanosis, hypoxia and increased TLC had

been reported upon examination of the patient. Going through the

algorithm, the experts responded “No” to questions II and III except the

answer to the question “Is there strong evidence against causal association?”

is positive because of acute onset of symptoms and clinical as well as

laboratory findings confirming pneumonia.

The group of AEFI causality experts, therefore, could conclude that

the classification is coincidental (pneumonia) most likely due to aspiration.

Increased TLC and long duration of illness exclude anaphylaxis. Toxic shock

syndrome is also excluded as this was an isolated case and no other child

developed any symptoms after vaccination with the same vial.

During the plenary, although Professor Noni MacDonald agreed with

the conclusions of the experts group, she recommended verifying the

hypothesis of anaphylaxis using the same revised causality assessment

methodology with the causality question “Has the pentavalent

vaccine/vaccination caused anaphylaxis?” There are no reports in the

literature of anaphylaxis with oral vaccines like OPV. It is also necessary to

consider whether a reaction to the vaccine contributed to the aspiration.


44

Group 3 – Case 1

Sex: Female

Date of birth: 9 June 2012

Address: Rural



1 Age at the day of

vaccination

3 days

2 Birth date 9 June 2012


vaccine

In two sessions: 10 June and 12 June 2012

4 Type of vaccine 10 June 2012 vaccine HepB lot no.0390929

expiry 9 April 2012

12 June 2012 vaccine BCG lot no.01310 exp.

2 September 2012 (in the afternoon, no exact

time recorded)

5 Place of vaccination District hospital

6 Date/time of onset of AEFI 12 June 2012 between 20:00 and 21:30

7 Date/time of death 12 June 2012 around 22:00

8 Health history The second child of a 29-year-old woman who is a

bank employee, attended for antenatal care at clinic,

regular delivery at provincial hospital, APGAR 9, 10,

10; weight at birth 3090 g. No unusual signs at birth,

left the hospital with mother

9 Symptom and treatment 12 June 2012

Went home with her mother, no fever, but the

mother reported that the child drinks milk very

little

20:00, when taking milk, the child choked, her

mother held her over the shoulder and put her to

bed and let her sleep with turned face alone


45


Around 22:00, mother noticed that the child

wasn’t moving, so she checked on her and found

out that the child’s face, legs, arms were green and

the child was not breathing. The child was brought

to the hospital. Nurses gave oxygen by mask and

did chest compressions, and then the doctor

inserted an ET tube and then milk came out in the

child’s mouth so the doctor did suction by using

ET tube. They got around 5cc of milk. The child

died.

Doctor diagnosed the child with respiratory arrest

(respiratory failure of newborn)



health facility

The seven children who received the same BCG

vaccine and the other child who receive the same

HepB vaccine did not experience unusual reactions.


12 Investigation of vaccine Vaccine wasn’t sent for investigation

13 Autopsy No autopsy

14 Investigation’s team

conclusions

From AEFI committee at regional level:

Unlikely because the death of the child matches

the death from hypoxiand milk found in the

mouth and ET tube, the death is likely to happen

because of choking. However, there are some

doubts:

Milk stain may come from chest compressions

before insertion of ET tube.

Vaccination may make a child drowsy and

then cause choking.

Suggestion:

Doctor should have sent for CXR after the death if

suspected aspiration including asking death scene

history and checking the milk stain on the child’s

body.

For newborns, when receiving vaccine, the child

should go home immediately, and the parent

should be advised to monitor their child.


46


The valid diagnostic used by the group is “respiratory failure”. They noted

that there is no Brighton case definition for respiratory failure but found it in

the paediatric advanced life support, where the case definition is “failure to

maintain oxygenation with simple measures – positioning and oxygen by

mask”. The participants then wrote down the causality question as “Has the

BCG vaccine/vaccination cause acute respiratory failure?”

In the revised causality assessment methodology questionnaire to

question I “Does clinical examination confirm another cause?” they

responded “Yes” because symptoms occurred after feeding and there is

milk present in the ET tube. Responses to all parts of question II were

negative. To question III “Is there strong evidence against a causal

association?” the group responded “Yes” because of the child’s history of

choking and presence of milk in the tube. In question IV “Other qualifying

factors for classification”, the group responded “yes” to both “Could the

event occur independently of vaccination?” because aspiration is not

uncommon among babies and the second question “Could the event be a

manifestation of another health condition?” because symptoms of

aspiration were present. Responses to all other parts of question IV were

negative.

The group conclusion was that this case is coincidental because there

is history as well as clinical evidence of milk aspiration leading to respiratory

failure. It is not anaphylaxis as BCG is not known to cause anaphylaxis. It

does not fit toxic shock syndrome as there are no clinical findings and no

other cases were reported. However, Hepatitis B expiry date had passed

and its efficacy might be lower than expected.

Professor MacDonald noted that drowsiness is not common after BCG

or HBV hence would not have contributed to aspiration.


47

Group 3 – Case 2

Sex: Male


Address: Rural



1 Age at the day of

vaccination

2 months and 3 days



vaccine

24 May 2012 at 10:00

4 Type of vaccine DTP-HepB-Hib 1 (Batch No 1452046) and OPV 1

(Batch No H5006)

5 Place of vaccination Health station, routine immunization

6 Date/time of onset of AEFI 24 May, 18:30 excessive crying

7 Date/time of death 24 May at 22.45 –13 hours after the vaccination

8 Health history No antenatal complications reported

Born in district hospital, born at term + 3 days, mode

of delivery normal, birth weight 2240 g. The child was

breastfed and was not hospitalized before the event.

The child received BCG, but there was no record on

the health card.

The child had two sisters four and eight years old with

no neonatal major illness reported by the father and

the mother. There is no history of infant death in the

family.

9 Symptom and treatment 24 May 18:30, child crying excessively, father sought

advice from the estate medical assistant (EMA) without

taking the child with him. EMA advised admission to

the hospital; baby was brought to the hospital and

admitted at 22.45 most probably due to delay in taking

a decision to seek medical care from hospital. (District

Hospital X is situated about 18 km away from

residence of parent and roads are in good condition.

EMA arranged transport facilities but father refused


48


saying that they are going by their own transport).

On the way to hospital, child’s crying reduced and the

child became unresponsive 15 minutes before reaching

hospital. At the time of the hospital admission at 22.45,

the child was pronounced dead.



health facility

No similar events were reported with other children

vaccinated (3) either with the same vaccine vial or

vaccine batch.

11 Vaccine management VVM was at stage 1 and no cold chain break down was

reported during the transportation of the vaccine.

12 Investigation of vaccine

13 Autopsy No written report available, awaiting the pathological

report

Personal communication with forensic medical

officer:

No macroscopic abnormality was found.

Histopathological examination: Cerebral oedema

and features of acute respiratory distress syndrome

Most probably death was not associated with the

immunization: may be atypical pneumonia.


conclusions

Coincidental. History and pathological observations

support the diagnosis of underlying acute infection.


The group identified “excessive crying” as the valid diagnostic and thus

established the causality question “Has the pentavalent vaccine/vaccination

caused excessive crying?” However, experts groups debated on the strong

evidence for other causes because autopsy findings revealed acute

respiratory distress and cerebral oedema.

Concerning question II “Is there a known causal association with the

vaccine?”, the participants of this group responded “Yes” because of

evidence in the literature that vaccine/vaccination may cause excessive

crying but it does not cause death. By going through questions III “Is there

strong evidence against causal association?” and IV “Other qualifying factors


49

for classification”, the group of experts concluded that with available

evidence the classification is coincidental, because the child had cough and

cold which evolved into acute respiratory distress. Respiratory distress

eventually causes cerebral oedema. These features were found at the

autopsy.

Professor Noni MacDonald pointed out that excessive crying can lead

to the parent shaking the baby in frustration – leading to shaken baby

syndrome with cerebral oedema. The medical team did not consider it

child abuse although the father’s actions were noteworthy.


50

Group 3 – Case 3

Sex: Female


Address: unknown



1 Age at the day of

vaccination

6 months 14 days



vaccine

28 May 2011 at 11:00

4 Type of vaccine Pentavalent DTP-HepB-Hib (2nd

dose) Lot No 0451421

expiry August 2013.

OPV no batch or expiry records

5 Place of vaccination NOT AVAILABLE

6 Date/time of onset of AEFI 29 May at 02:00

7 Date/time of death 29 May at 03:30

8 Health history Normal vaginal delivery. Birth weight 1800 kg. The

baby was exclusively breastfed for four months. No

hospitalization, no allergy, no congenital abnormality.

Received previous immunization with BCG pentavalent

and OPV with no report of AEFI.

9 Symptoms and treatment 29 May 2011 at 02:00 child cried, breathed loudly and

abdominal distension noted. Mother tried to breast

feed but child refused. She tried to give paracetamol

syrup ½ teaspoon but child refused to take.

At 03:35, the child was admitted to the district hospital

paediatric ward. Pulse 90/m, RR 56/m, irregular,

cyanosis, cold extremes, abdomen distended. CPR

initiated immediately IV saline, adrenaline 0.3 n=ml

(1:10 000), repeated after 10 minutes. Child improved

but cardiac arrest at 5:00, CPR done.

At 5:30, the child was dead.


51




health facility

61 children were vaccinated in the same clinic the

same day, out of which 35 were vaccinated with the

same vaccine. No similar events were reported.

11 Vaccine management No cold chain breakdowns were reported and the VVM

on the incriminated vaccines was stage 1.

12 Investigation of vaccine Not available

13 Laboratory/Autopsy In the district hospital, autopsy was conducted by the

forensic medical officer. No features of any

allergic/anaphylactic reaction were noted. Congenital

heart disease comprising: truncus arteriosus, absent

pulmonary artery, VSD, RV hypertrophy, dilated RA.


conclusion

Cause of death: Congestive cardiac failure following

congenital heart disease


The valid diagnostic used by the group is shock. There is no Brighton case

definition for shock. The participants then stated their question as “Has the

pentavalent and/or OPV vaccine caused shock?”

The answer to question I “Is there strong evidence for other causes?”

is positive because the autopsy showed truncus arteriosus, absent

pulmonary artery, VSD, RV hypertrophy and dilated RA. The responses to

all parts of question II were negative and for question III “Is there strong

evidence against a causal association?” participants responded “yes”

because autopsy showed complicated congenital heart disease. To question

IV “Could the event occur independently of vaccination?” and “Could the

event be a manifestation of another health condition?” the participants

responded “Yes” because many conditions can cause shock and because of

the complicated congenital heart disease the child had at the time of the

vaccination. All the other answers in questions IV were negatives.

Therefore, in light of the information collected during the

investigation, this group conclusion is coincidental because of underlining

complicated heart disease.

Professor MacDonald concurred. Also noted that the baby had low

birth weight.


52

Annex 6

Questionnaire to assess usefulness of causality

algorithm tools to participants

Worksheet for AEFI causality assessment

Step 1 (Eligibility)

Do you think the above step is helpful? Yes No No opinion

If “No” – Please suggest modifications by writing on the figure above and/

or providing suggestions below.

1.

2.

3.

Name of the

Patient

Name of one or

more vaccines

administered

before this event

What is the valid

diagnosis?

Does the diagnosis

meet a case

definition?

Create your question on causality here

Has the ___________ vaccine / vaccination caused ______________? (The event for

review in step 2)


53

Is the above causality question helpful? Yes No No opinion



1.

2.

3.

Step 2 (Event checklist) (check) all boxes that apply

I. Is there strong evidence for other causes? Y N UK NA Remarks

Does a clinical examination, or laboratory tests on the patient,

confirm another cause?

II. Is there a known causal association with the vaccine or vaccination?

Vaccine product(s)

Is there evidence in the literature that this vaccine(s) may cause the

reported event even if administered correctly?

Did a specific test demonstrate the causal role of the vaccine or any

of the ingredients?

Immunization error

Was there an error in prescribing or non-adherence to

recommendations for use of the vaccine (e.g. use beyond the expiry

date, wrong recipient etc.)?

Was the vaccine (or any of its ingredients) administered unsterile?

Was the vaccine's physical condition (e.g. colour, turbidity, presence

of foreign substances etc.) abnormal at the time of administration?

Was there an error in vaccine constitution/preparation by the

vaccinator (e.g. wrong product, wrong diluent, improper mixing,

improper syringe filling etc.)?

Was there an error in vaccine handling (e.g. a break in the cold chain

during transport, storage and/or immunization session etc.)?

Was the vaccine administered incorrectly (e.g. wrong dose, site or

route of administration; wrong needle size etc.)?

Immunization anxiety

Could the event have been caused by anxiety about the

immunization (e.g. vasovagal, hyperventilation or stress-related

disorder)?


54

II (time). If “yes” to any question in II, was the event within the time window of increased risk?

Did the event occur within an appropriate time window after vaccine

administration?

III. Is there strong evidence against a causal association?

Is there strong evidence against a causal association?

IV. Other qualifying factors for classification

Could the event occur independently of vaccination (background

rate)?

Could the event be a manifestation of another health condition?

Did a comparable event occur after a previous dose of a similar

vaccine?

Was there exposure to a potential risk factor or toxin prior to the

event?

Was there acute illness prior to the event?

Did the event occur in the past independently of vaccination?

Was the patient taking any medication prior to vaccination?

Is there a biological plausibility that the vaccine could cause the

event?

Y: Yes N: No UK: Unknown NA: Not applicable

Are these questions useful? Yes No No opinion

If “No” – Please suggest modifications by writing on the checklist above

and/ or providing suggestions below.

1.

2.

3.

Are there situations where the checklist does not work? Yes No No

opinion How could they be fixed?

If “Yes” – Please suggest modifications by writing on the figure above and/


1.

2.

3.


55

Step 3 (Algorithm) review all steps and all the appropriate boxes

Is step 3 algorithm helpful in this the causality assessment process?

Yes No No opinion



1.

2.

3.

Notes for Step 3:


56

Step 4 (Classification) all boxes that apply

Is the step 4 classification useful? Yes No No opinion


or providing suggestions below

1.

2.

3.

Summarize the classification logic: With available evidence, we could conclude that the classification is

___________________________________because:


57

Do you find the above summary step useful? Yes No No opinion


or providing suggestions below

1.

2.

3.

If you have any suggestion for another format or a modification, e.g .a new

section on recommendations etc., please suggest and provide brief details.

Do you have any other general suggestions to improve causality assessment

process in your country? E.g. special studies, select communication issues,

training issues, verbal autopsy etc.

You are with the EPI / NRA / Clinician / Other – specify

_______________________

Number of years of experience with AEFI

_____________________________


58

Annex 7

Plenary discussions

Day 3: Summary comments

(1) What are we going to do with what have we learned at the

workshop?

To adapt and to use the material for causality committee

updates and to develop teaching material for training

workshops on causality assessment. Guidelines on AEFI

monitoring need to be updated in several countries to

include new definitions.

(2) What have we learned in this process?

The value of learning together and the opportunity to

exchange experience among countries in the South-East Asia

and Western Pacific regions.

Importance of laboratory investigation and collection of

quality data, although there are significant constraints in

many countries on post-mortem autopsy.

Need to strengthen procedures with standing operating

procedures/guidelines in countries where post-mortem

autopsy is performed. From the eight AEFI cases reviewed

during working group sessions, those with post-mortem

autopsy, the findings contributed significantly to establish

causal association with the vaccine administered, for

example, the GBS case.

Need to define criteria for SIDS case autopsy in this

low/middle income setting.

Need to use verbal autopsy – caretaker, parents,

practitioners and streamline field investigation procedures.

AEFI investigation teams should include clinicians, especially

paediatricians from outside of the NIP. This is a confidence

issue for parents and local health- care workers.


59

(3) What are the suggestions for research studies?

Need background rates for VPD, for example, pertussis.

Need background rates for AEFI with Penta, for example,

excessive crying and seizures

Need background rates for SIDS. India has prospective study

ongoing of 40 000 children that may provide some regional

data on SIDS.

Need to learn about the immunization of children with

congenital heart disease. For congenital heart disease, the

paediatric associations might work to develop a strategy to

increase early detection of clinically significant cases. This is

a challenge in many countries as the immunizer has very

limited health-training background. A set of simple questions

to be asked by the vaccinator could help to identify such

children. Recommendation: Approach paediatric societies in

the Region to see if they could develop a practical set of

questions and observations for detection of coronary heart

disease for referral (still immunize).

(4) Combined measles rubella vaccine was given to > 53 million in

Bangladesh- an opportunity to see AEFI on big population vs.

background rates of events. (Bangladesh provided to WHO AEFI

data during the measles and rubella vaccination campaigns to

help to prepare a summary presentation of findings).

(5) How can the NRA become more involved?

Thailand has NRA representative at the National AEFI

committee.

(6) Participants noted that in countries procuring vaccines through

UNICEF, the NRA has very limited capacity to review vaccine

dossiers for a full licensing. WHO has developed for those

countries a guideline – Procedure for expedited review of

imported prequalified vaccines for use in national immunization

programmes – which describes the procedure for the market

authorization of vaccines supplied through UN procurement

agencies, that is, WHO pre-qualified vaccines. It includes a

simplified lot release procedure for the NRA in the receiving

country to perform a visual check of the product and to review


60

documents in the packing list to verify compliance with

specifications in the national tender. This expedited procedure

aims to enhance NRA product knowledge and to encourage

NRAs/NCLs to maintain small dossiers of essential information on

each lot to be consulted in case of serious AEFI.

Recommendation: a small survey to identify to what extent the

NRA is involved in AEFI in each of the participating countries.

(7) To the question “Do you find the Brighton definitions useful?”,

the participants responded positively; however, definitions need

to be adapted to LMIC immunization settings, for example,

diagnosis of fever needs a thermometer, yet no thermometer is

available in many LMIC sites where vaccine is administered. The

participants also identify the need to expand definitions to cover

pneumonia and septic shock, taking into account basic

equipment for diagnosis available in LMICs. Recommendation:

Request a formal review of Brighton definition to develop

definitions levels that will work in settings where no equipment

and limited health-worker training (for example, outside of a trial

in the real LIC world).

(8) Time interval for when to expect AEFI with different vaccines is

very helpful for AEFI causality assessment. Some Brighton

definitions have this – some do not. Recommendations: To

explore development of a practical tool – definition, time interval,

rates AEFI with different vaccines.

(9) To the question “Do you find the WHO vaccine position papers

useful?”, most participants responded it was helpful to have short

abstract or tables containing essential information. There is a

need to make contraindications of use with other vaccines easier

to find. A WHO position paper on subsequent immunization

would be helpful.

(10) Vaccine compensation programmes are starting to appear in the

Region, for example, in Indonesia; other countries are interested

but raised concerns as well. Recommendation: It would be

helpful to have the 10 countries get together to review

compensations schemes – pros, cons, strategies and assess what

might work in the Region – not just extrapolate from high income

country experiences.


61

(11) Analysis and causality assessment are priority areas, especially as

more AEFI are detected and being reported. There is a need to

ensure these analyses are translated into helpful, not harmful,

messages for public and politicians.

(12) The value and importance of AEFI detection and quality causality

assessments needs to be taught in medical and nursing schools.

The National Medical Council may be the entry point – need to

identify procedure to update curriculum. Recommendation:

Explore how immunization and AEFI can be better incorporated

into medical school curriculum (and nursing school).

(13) Need for advocacy for AEFI and causality assessment – especially

for policy-makers.

(14) India is changing the name of its AEFI committee to Vaccine

Safety Committee; NB “Vaccine pharmacovigilance “ is jargon

and not understood easily by public or politicians

(15) What next? All the participants appreciated the use of AEFI cases

from the Region; they found the country presentations to be very

informative. The size of the meeting was suitable but if the

number of participants increases, we will need to increase the

number of working groups and thus the number of facilitators.

Participants proposed to conduct this meeting in the Region once

every year or every two years.

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