Ethiopian Food and Drug Authority

ETHIOPIAN FOOD AND DRUG AUTHORITY

PHARMACOVIGILANCE AND CLINICAL TRIAL LEAD EXECUTIVE

OFFICE

National Guideline for Monitoring Adverse Events

Following Immunization

Document No.: EFDA/GDL/016 Version No: 004

Date of approval: 03 June Date of First issue: 25 June

Document History

Version No. Reason for Amendment Effective Date

001 New version January, 2005

002 Revised to include investigation techniques, specimen collection, February, 2016
managing AEFIs and communicating with the media, bring
stakeholders together and allow for networking and improved
collaboration in the process of detecting, analysing and preventing
AEFIs.
003 Amended to incorporate the roles and responsibilities of some February, 2018
stakeholders in AEFI reporting and investigation, clearly indicates
AEFI reporting route and timeline, analysis of AEFI data and also
includes Communication and media management

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004 Revised to provides complete guidance on the detection and June, 2024
reporting of AEFI, channels of reporting of AEFIs, investigation
and causality assessment of AEFI cases. Includes all antigens given
in Ethiopia even in routine immunization programs Moreover, it
incorporates roles and responsibilities of all AEFI stakeholders at
all levels to take active part in the strengthening of the AEFI
surveillance system in Ethiopia and vaccine safety and risk
communication strategy

Asnakech Alemu, Signature

Page I of 90

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Table of Contents
Foreword .......................................................................................................................................... i
Acknowledgements ........................................................................................................................ iii
Glossary .......................................................................................................................................... v
Abbreviation and/or Acronyms.................................................................................................... viii
List of Tables ................................................................................................................................. ix
List of Figures ................................................................................................................................. x
Introduction ..................................................................................................................................... 1
1.1. Background ..................................................................................................................... 1
1.2. Scope ............................................................................................................................... 2
1.3. Objective ......................................................................................................................... 2
[Link] Concepts of Vaccines and Adverse Events Following Immunization ............................... 3
2.1. Vaccines .......................................................................................................................... 3
2.1.1. Classification of vaccines ........................................................................................... 3
2.1.2. Other components of vaccines .................................................................................... 6
2.1.3. Contraindications and precautions to vaccination ...................................................... 7
2.2. Adverse Events Following Immunization ...................................................................... 7
2.2.2. Immunization error-related reactions ........................................................................ 13
[Link] and management of AEFI ........................................................................................ 16
3.1. General principles of prevention and management of AEFI ........................................ 16
3.2. Prevention and management of immunization error-related reactions ......................... 16
3.3. Prevention and management of immunization anxiety-related reactions ..................... 18
3.4. Management of suspected anaphylaxis or collapse after vaccination .......................... 19
[Link] Events Following Immunization Surveillance System in Ethiopia ............................. 21
4.1. Objectives of AEFI Surveillance System ..................................................................... 22
4.2. Types of AEFI Surveillance System ............................................................................. 23
4.3. AEFI Detection and Reporting ..................................................................................... 24
4.3.1. Components of AEFI Reporting ............................................................................... 24
4.3.2. Reporting AEFIs during immunization campaigns .................................................. 26
4.4. Investigating AEFIs ...................................................................................................... 28
4.4.1. Objectives of AEFI investigation.............................................................................. 28
4.4.2. What should be investigated? ................................................................................... 28
4.4.3. Who should be involved in AEFI investigation? ...................................................... 29
4.4.4. When to investigate? ................................................................................................. 29
4.4.5. How to investigate?................................................................................................... 29
4.4.6. Investigation of AEFI with fatal outcome ................................................................ 32
4.4.7. Investigating AEFI clusters....................................................................................... 32
4.4.8. Laboratory testing of specimens ............................................................................... 33
4.5. AEFI causality assessment ............................................................................................ 34
4.5.1. Levels of AEFI causality assessment ........................................................................ 35
4.5.2. Criteria for causality in the causality assessment process ........................................ 36
4.5.3. Who should do causality assessment? ...................................................................... 36
4.5.4. Case selection for causality assessment .................................................................... 37
4.5.5. Prerequisites/ basic requirements for causality assessment ...................................... 37

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 4.5.6. Steps for causality assessment of AEFI .................................................................... 38
4.5.7. Actions to be taken after causality assessment. ........................................................ 42
4.6. Action and response to AEFI ........................................................................................ 44
4.6.1. Patient care ................................................................................................................ 45
4.6.2. Follow-up actions...................................................................................................... 45
4.6.3. Logistics .................................................................................................................... 46
[Link] Data Management ............................................................................................................ 46
5.1. Sources of AEFI data .................................................................................................... 47
5.2. Data entry ...................................................................................................................... 48
5.3. Data Analysis and Interpretation .................................................................................. 48
5.3.1. Responsible body for data analysis at different levels .............................................. 49
5.3.2. Steps in AEFI data analysis and interpretation ......................................................... 50
5.3.3. Consideration of causality......................................................................................... 54
[Link] in AEFI Monitoring.............................................................................................. 55
6.1. Roles and Responsibilities of key stakeholders ............................................................ 56
6.1.1. MOH/National Immunization Program .................................................................... 56
6.1.2. Ethiopian Food and Drug Authority (EFDA) ........................................................... 56
6.1.3. Ethiopian Public Health Institute (EPHI) ................................................................. 57
6.1.4. Regional EPI and Regulatory bodies ........................................................................ 58
6.1.5. Woreda and Zonal EPI and regulatory bodies .......................................................... 58
6.1.6. EFDA Branch Offices ............................................................................................... 59
6.1.7. Regional Pharmacovigilance Centres (RPVCs)........................................................ 59
6.1.8. National Pharmacovigilance Advisory Committee (NPAC) .................................... 59
6.1.9. The parent/guardian .................................................................................................. 60
6.1.10. The health professionals ....................................................................................... 60
6.1.11. Developmental Partners ........................................................................................ 61
[Link] Communication............................................................................................................... 62
7.1. Vaccine safety communication during crisis ................................................................ 63
7.2. Communication with stakeholders ................................................................................ 63
7.2.1. Communication with clients, parents/guardians and the community ....................... 64
7.2.2. Role of health professionals in community communication on AEFI ...................... 64
7.2.3. Communication with health professionals ................................................................ 65
7.2.4. Communicating with community and/or religious leaders ....................................... 65
7.3. Communicating with the Media.................................................................................... 65
7.4. Follow-up actions with communications ...................................................................... 67
[Link] and Evaluation of AEFI Surveillance system ......................................................... 68
8.1. Monitoring arrangements/ platforms ............................................................................ 68
8.2. AEFI monitoring Indicators. ......................................................................................... 69
[Link] .................................................................................................................................. 71
[Link].................................................................................................................................... 72

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Foreword

Vaccines are principally used to protect individuals predominantly children from acquiring deadly
infectious diseases which are vaccine preventable. Modern vaccines are generally safe and
effective. However, they may cause Adverse Events Following Immunization (AEFI). An AEFI
may be caused by a vaccine reaction, or it may be caused by an error in administration or handling
of the vaccine. It may also be due to anxiety related reaction or coincidental event. Most of the
AEFIs are mild or moderate but sometimes serious AEFIs may happen. As vaccines are usually
given to healthy individuals, there is low public tolerance to AEFIs. AEFIs may lead to public
suspicions of vaccines and parents may refuse further immunization for their children. Hence,
monitoring AEFI is of paramount importance in a healthcare system of any country as this helps
sustain public confidence in the immunization program.

AEFI surveillance system utilizes different tools such as guidelines, AEFI recording and reporting
tools, and procedures geared to assure public health protection using vaccines with proven safety
profile. In Ethiopia, the current system for monitoring medicine safety (pharmacovigilance) is
coordinated by the Ethiopian Food Drug Authority (EFDA), the National Regulatory Authority
(NRA) mandated by proclamation 1112/2019 to ensure the safety, quality and efficacy medicines
and other medical technologies.

EFDA has been working to improve patient care and safety in relation to the use of medicines and
other medical interventions in collaboration with various stakeholders. It is essential that all
stakeholders including the Expanded Programme on Immunization (EPI), Ethiopian Public Health
Institute (EPHI), vaccine manufacturers, laboratories, healthcare providers and development
partners make rigorous efforts to provide documented evidence on vaccine safety through an
effective AEFI surveillance system. This will ensure the provision of best immunization services
to the community including effective monitoring and response to AEFIs.

It is envisaged that this guideline provides complete guidance on the detection and reporting of
AEFIs; channels of reporting of AEFIs; investigation and causality assessment of AEFI cases.
Moreover, it guides all AEFI stakeholders at all levels to take active part in the strengthening of
the AEFI surveillance system in Ethiopia.

It is with great pleasure to present this revised (4th edition) Guideline for Monitoring of AEFI in
Ethiopia. I hope all stakeholders will use this guideline effectively as a guide towards maintaining
vaccine safety and ultimately improve immunization programme.

Finally, I would like to take this opportunity to thank all individuals, institutions/organizations and
partners involved in the revision, printing and distribution of this guideline. I would also like to

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call upon all interested bodies/individuals to continue their usual support through forwarding their
comments and suggestions for improvements to the Ethiopian Food and Drug Authority through
P.O. Box 5681 Addis Ababa, Ethiopia, Tel.251-115524122, e-mail contactefda@[Link].

Heran Gerba

Director General, EFDA

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Acknowledgements
EFDA would like to acknowledge the World Health Organization (WHO), the Ohio State
University Global One Health Initiative (GOHi), and the USAID Global Health Supply Chain
Program-Procurement and Supply Management (GHSC-PSM) for their financial and technical
support during the revision of this guideline. The Authority would also like to extend its gratitude
to all participants of the validation workshop for their valuable comments and contributions.
Finally, EFDA extends its heartfelt appreciation and gratitude to the experts listed below for their
professional and scientific contributions in the development and revision of this guideline.

Name Institution

Aida Arefayne USP-PQM+

Asnakech Alemu EFDA

Assefa Ejamo EFDA

Belete Ayaneh GHSC-PSM

Demeke Amare EFDA

Dr Elizabeth Woldemariam EFDA/TBI

Dr. Hilina Worku WHO

Dr. Shemsu Umer EFDA

Dr. Yalemzewud Ankela EFDA

Dr. Zelalem Aysheshim EFDA

Habtamu Gashaw EFDA

Kassech Sintayehu Ohio State Global One Health

Mehiret Maru EFDA

Melkamu Adigo EFDA

Merkeb Aytenfisu EFDA

Meron Kifle EFDA

Solomon Getnet Ohio State Global One Health

Tesfaye Anosie EFDA

Teshita Shute EFDA

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Tigist Dires EFDA

Wondie Alemu GHSC-PSM

Workagegnehu Degefe EFDA

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Glossary

AEFI Any untoward medical occurrence which follows immunization,

and which does not necessarily have a causal relationship with the
usage of the vaccine. The adverse event may be any unfavourable
or unintended sign, abnormal laboratory finding, symptom or
disease.

Causal association A cause-and-effect relationship between a causative (risk) factor

and an outcome. Causally associated events are also temporally
associated (i.e. they occur after vaccine administration), but events
which are temporally associated may not necessarily be causally
associated.

Causality assessment In the context of AEFI surveillance, it is a systematic review of data

about AEFI case(s) to determine the likelihood of a causal
association between the event and the vaccine(s) received.

Cluster Two or more cases of the same or similar events related in time,
geography (place), and/or vaccine administered. AEFI clusters are
usually associated with a particular supplier/provider, health.

facility, and/or a vial of vaccine or a batch of vaccines.

Coincidental events An AEFI caused by something other than the vaccine product,
immunization error or immunization anxiety.

Contraindication A situation where a particular treatment or procedure, such as

vaccination with a particular vaccine, must not be administered for
safety reasons. Contraindications can be permanent (absolute),
such as known severe allergies to a vaccine component, or
temporary (relative), such as an acute/ severe febrile illness.

Crisis communication Is an adjusted response to an incident, which aims to restore public

confidence by informing the public on what went wrong, why, and
what is being done in response.

Immunity The ability of the human body to tolerate the presence of material
‘indigenous’ to the human “body” (self) and to eliminate “foreign”
(non-self) material. This discriminatory ability provides protection

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 from infectious diseases since most microbes are identified as
foreign by the immune system.

Immunization An AEFI arising from anxiety about the immunization.

anxiety-related
reaction

Immunization error- An AEFI caused by inappropriate vaccine handling, prescribing or

related reaction administration and thus by its nature is preventable.

Immunization safety The process of ensuring the safety of all aspects of immunization,
including vaccine quality, adverse events surveillance, vaccine
storage and handling, vaccine administration, disposal of sharps
and management of waste.

Injection safety The public health practices and policies dealing with various
aspects of the use of injections (including adequate supply,
administration and waste disposal) so that the provider and
recipient are not exposed to avoidable risks of adverse events (e.g.,
transmission of infective pathogens) and creation of dangerous
waste is prevented. All injections, irrespective of their purpose, are
covered by this term (see definition of safe injection practices).

Monitoring Monitoring is a continuous assessment that aims at providing all

stakeholders with early detailed information on the progress or
delay of the on-going assessed activities.

Non-serious AEFI An event that is not ‘serious’ and does not pose a potential risk to
the health of the recipient. Non-serious AEFIs also should be
carefully monitored because they may signal a potentially larger
problem with the vaccine or immunization or have an impact on the
acceptability of immunization in general.

Risk Communication Is enable people at risk to take informed decisions to protect

themselves and their loved ones.

Safe injection Practices which ensure that the process of injection carries the
practice minimum of risk, regardless of the reason for the injection or the
product injected.

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Serious AEFI An event that results in death, is life-threatening, requires in-patient
hospitalization or prolongation of existing hospitalization, results
in persistent or significant disability/incapacity, or is a congenital
anomaly/birth defect. Any medical event that requires intervention
to prevent one of the outcomes above may also be considered as
serious.

Severe/Severity The term severe is not synonymous with serious in this context.
Severe is used to describe the intensity (severity) of a specific event
(as in mild, moderate or severe myocardial infarction).

Signal (safety signal) Information (from one or multiple sources) which suggests a new
and potentially causal association, or a new aspect of an own
association, between an intervention and an adverse event or set of
related adverse events, which is judged to be of sufficient likelihood
to justify verificatory action.

Surveillance The continuing, systematic collection of data that will be analysed

and disseminated to enable decision-making and action to protect
the health of populations.

Vaccine A biological preparation that improves immunity to a particular

disease. In addition to the antigen, it contains multiple components
(excipients), and each component may have unique safety
implications.

Vaccine The science and activities relating to the detection, assessment,

pharmacovigilance understanding and communication of AEFI and other vaccine- or
immunization-related issues, and to the prevention of untoward
effects of the vaccine or immunization.

Vaccine reaction An event caused or precipitated by the active component or one of

the other components of the vaccine. It may also relate to a vaccine
quality defect.

Vaccine safety The process, which maintains the highest efficacy of and lowest
adverse reaction to a vaccine by addressing its production, storage
and handling. Vaccine safety is a part of immunization safety.

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Abbreviation and/or Acronyms

ADR adverse drug reaction

AEFI adverse events following immunization

ANC antenatal care

BCG Bacillus Calmette Guerin vaccine for tuberculosis

CIOMS Council for International Organizations of Medical Sciences

COVID-19 Corona Virus Disease 2019

DT Diphtheria and Tetanus vaccine

DTaP Diphtheria, Tetanus and acellular Pertussis vaccine

Diphtheria, Tetanus, acellular Pertussis, Hepatitis B and Haemophilus influenza

DTPa-HepB-Hib
vaccine

DTwP Diphtheria, Tetanus, and whole cell Pertussis vaccine

EFDA Ethiopian Food and Drug Authority

EPHI Ethiopian Public Health Institute

EPI Expanded Program on Immunization

EPSS Ethiopian Pharmaceuticals Supply Service

GACVS Global Advisory Committee on Vaccine Safety

GVAP Global Vaccine Action Plan

Hep B Hepatitis B vaccine

Hib haemophilus influenza type b vaccine

ICSR Individual Case Safety Report

IPV Inactivated Polio Vaccine

LAV Live Attenuated Vaccine

MAH Marketing Authorization Holder

MMR Measles, Mumps and Rubella vaccine

MOH Ministry of Health

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 NRA National Regulatory Authority

OPD Outpatient Department

OPV Oral Polio Vaccine

List of Tables

Table 1: Types of subunit vaccines. ...................................................................................... 5

Table 2: Cause-specific type of AEFIs. ................................................................................. 7

Table 3: Frequency of occurrence of reported adverse reactions. .......................................... 9

Table 4: Common and very common minor vaccine reactions by antigen type. .................... 9

Table 5: Serious vaccine reactions, onset interval and frequency. ....................................... 12

Table 6:Immunization error-related reactions. .................................................................... 13

Table 7: Conditions that may be mistaken for anaphylaxis post-immunization. .................. 19

Table 8:Adrenaline dosing and administration for treatment of anaphylaxis. ...................... 20

Table 9: Core variables: minimum information required for reporting in AEFI surveillance.
.................................................................................................................................... 25

Table 10: Steps of AEFI Investigation and actions taken at each step. ................................ 30

Table 11: Laboratory testing to investigate AEFIs by working hypothesis.......................... 34

Table 12: Actions to be taken upon completion of the investigation/causality assessment. . 45

Table 13: Types and purpose of data analysis at different levels. ........................................ 49

Table 14: Options for selecting a denominator.................................................................... 51

Table 15: Terminology and interpretation on type of rates. ................................................. 52

Table 16: Factors to consider when comparing rates of AEFIs. .......................................... 53

Table 17: Media plan for communication. .......................................................................... 66

Table 18: Brief description on M&E Key Performance Indicators for AEFI ....................... 70

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List of Figures

Figure 1: AEFI Surveillance Cycle ..................................................................................... 22

Figure 2: AEFI Reporting Route, Timeline and Actions. .................................................... 27

Figure 3: Identifying cause of AEFI cluster ........................................................................ 33

Figure 4: Case’s eligibility for causality assessment ........................................................... 39

Figure 5: Causality assessment algorithm ........................................................................... 41

Figure 6: Causality assessment classification ...................................................................... 42

Figure 7: Data management cycle ....................................................................................... 47

Figure 8: Vaccine reaction rate, observed rate and background rate ................................... 53

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1. Introduction

1.1. Background

The immunization program is one of the most cost-effective health interventions, with proven
strategies to reach the most hard-to-reach and vulnerable populations. The overall goal of the
immunization program is to protect the health and wellbeing of the entire population, including
infants, children, adolescent girls, and pregnant women, from vaccine-preventable diseases. The
World Health Assembly’s Immunization Agenda 2030 envisions a world where everyone,
everywhere, at every age, fully benefits from vaccines to improve health and well-being.

In Ethiopia, the immunization program has achieved a remarkable reduction in morbidity and
mortality from vaccine-preventable diseases. The antigens in the routine immunization program
protect against diphtheria, pertussis, haemophilus influenzae type B, hepatitis B, tetanus, polio,
tuberculosis, pneumococcus, rotavirus, measles, human papillomavirus, and COVID-19. Newly
introduced vaccines also target diseases such as hepatitis B, cholera, malaria, meningococcal
meningitis A, and yellow fever.

Vaccines are biological substances administered to elicit immunity against specific diseases. These
products are formulated with adjuvants and/or excipients and, like all medical products, may cause
adverse events following their administration. There is no such thing as a "perfect" vaccine that
protects everyone and is entirely safe for all. Like other medicinal products, vaccines are not free
from adverse events.

An AEFI is any untoward medical occurrence that follows immunization and does not necessarily
have a causal relationship with the vaccine. If not rapidly and effectively addressed, AEFI can
undermine confidence in a vaccine and ultimately impact immunization coverage and disease
incidence. AEFIs can arise due to a variety of reasons, including events inherent to the vaccine
product, issues related to quality, immunization error, immunization anxiety, or coincidental
occurrences.

The World Health Organization (WHO) Global Advisory Committee on Vaccine Safety has
indicated the AEFI surveillance system as a key component of global AEFI reporting and part of
the Global Vaccine Action Plan Monitoring and Evaluation framework. This system serves as a
benchmark for evaluating vaccine safety performance at national, regional, and global levels and
monitoring progress in AEFI surveillance across all age groups. Although AEFIs are mostly mild
and rarely serious, measures need to be implemented to monitor and prevent their occurrence and
to take appropriate regulatory actions if necessary.

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EFDA is mandated by Proclamation No. 1112/2019 to regulate and protect public health by
ensuring the safety, efficacy, and quality of vaccines. EFDA has established pharmacovigilance
and post-marketing surveillance systems to assure vaccine safety. It sets out procedures for
reporting, analysing, and providing feedback on vaccine safety data from all key stakeholders in
the vaccine supply chain. Reporting AEFIs and subsequent investigation may lead to regulatory
actions, including withdrawing the marketing authorization of a vaccine, instructing manufacturers
to change product labels, restricting the use of vaccines to specific groups, or recalling defective
vaccine batches from the market. Thus, a robust AEFI monitoring system is essential for detecting,
managing, and preventing AEFIs.

Purpose
This guideline describes the process of AEFI detection, notification, reporting, investigation, data
management, causality assessment and feedback provision. In addition, it describes the roles and
responsibilities of all stakeholders, provides tools and procedures needed to report and manage
AEFIs and guides vaccine safety and risk communication strategies in the implementation of
vaccine pharmacovigilance system. It also serves as a reference material for healthcare providers,
regulators, expanded program on immunization (EPI) and other program managers.

1.2. Scope

This guideline applies to monitor AEFI surveillance activities from National Immunization
Program (NIP), and it applies to all stakeholders involved in AEFI monitoring system at all levels.

1.3. Objective

The objective of this guideline is to:

• Provide guidance on detection, management, reporting, investigation, data management,

casualty assessment, prevention and feedback provision on AEFI.
• Identify stakeholders involved in AEFI monitoring system and define their roles and
responsibilities.
• Provide guidance on the different tools used in the AEFI monitoring system.
• Provide guidance on effective vaccine safety and risk communication.

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2. Basic Concepts of Vaccines and Adverse Events Following Immunization

2.1. Vaccines

A vaccine is a biological product that produces and enhances immunity to the particular vaccine-
preventable diseases (VPDs) for which it is targeted. A vaccine contains the disease-causing
microorganism or virus, or a portion of it, in a form that is incapable of causing the actual disease.
It is usually made from either live attenuated or inactivated (killed) forms of the microbe or from
its toxin or one of its surface proteins. A vaccine can also be made from a messenger RNA (mRNA)
coding for an antigenic protein that is generated in vitro and encased with suitable material to
ensure delivery into the cell.

Vaccines may be monovalent or multivalent (polyvalent). A monovalent vaccine contains a single

strain of a single antigen or immunogen (e.g., measles vaccine), whereas a polyvalent vaccine
contains two or more strains or serotypes of the same antigen or immunogen (e.g., bivalent oral
polio vaccine [bOPV] and inactivated polio vaccine [IPV], each of which contains two live and
three attenuated poliovirus types, respectively).

Combination vaccines contain two or more different antigens (e.g., Td, DTPa-HepB-Hib). The
potential advantages of combination vaccines include reducing the cost and difficulty of shipping,
storing, and administering multiple vaccines, avoiding multiple injections, reducing the cost of
extra health-care visits, improving the timeliness of vaccination, and facilitating the addition of
new vaccines into immunization programs. Combining antigens usually does not increase the risk
of adverse reactions and can lead to an overall reduction in adverse reactions. For instance, it can
decrease the number of anxiety-related reactions and the chances of immunization error-related
reactions.

2.1.1. Classification of vaccines

There are different types of vaccines, such as live attenuated, inactivated (killed antigen), subunit
(purified antigen), toxoids (inactivated toxic compounds), viral vector-based vaccines, and nucleic
acid vaccines (messenger RNA and DNA vaccines). The characteristics of these vaccines differ,
and these characteristics determine how the vaccine works.

Live Attenuated Vaccine (LAV): Live attenuated vaccines (LAVs) are derived from “wild,” or
disease-causing, viruses or bacteria. These wild viruses or bacteria are attenuated, or weakened, in
a laboratory, usually by repeated culturing. The resulting vaccine organism retains the ability to
replicate (grow) in the vaccinated person and produce immunity but usually does not cause illness.

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The immune response to a LAV is virtually identical to that produced by a natural infection. For
LAVs, the first dose usually provides protection, and an additional dose is given to ensure
seroconversion. Immunity following live vaccines is long-lasting, and booster doses are generally
not necessary, except for the oral polio vaccine, which requires multiple doses.

LAVs are labile and can be damaged or destroyed by heat and light, so they must be handled and
stored carefully. One inherent problem of live attenuated vaccines is the potential for reversion to
the virulent strain; however, this risk is considerably minimized because multiple mutations are
usually introduced.

Globally, available LAVs include vaccines for measles, mumps, rubella, varicella, yellow fever,
oral polio, and influenza (intranasal). Live attenuated bacterial vaccines include BCG and oral
typhoid vaccines.

Inactivated whole-cell vaccines are produced by growing viruses or bacteria in culture media and
then inactivating them with heat or chemicals (usually formalin). Because they are not alive, they
cannot grow in a vaccinated individual. Inactivated vaccines are generally safer than LAV, with
no risk of inducing the disease. Unlike live antigens, inactivated antigens are usually not affected
by circulating antibodies. They are often more stable than LAVs. Inactivated vaccines always
require multiple doses. In general, the first dose does not produce protective immunity, but only
“primes” the immune system. A protective immune response is developed after multiple
subsequent doses. In contrast to live vaccines, in which the immune response closely resembles
natural infection, the immune response to an inactivated vaccine is mostly humoral and little or no
cellular immunity results.

Some of the safety issues that may need to be considered for inactivated vaccines include
incomplete inactivation of viral particles causing the vaccine to retain virulence and cause disease,
and development of vaccine-associated enhanced disease (VAED) when vaccinated individuals
encounter the pathogen after being vaccinated. Some of the currently available inactivated
vaccines include inactivated poliovirus vaccine (IPV), hepatitis A, anti-Rabies and etc.

Subunit vaccines: sometimes called acellular vaccines contain purified proteins/sugar of disease-
causing organism that stimulates immune cells. Subunit vaccines are considered very safe because
these purified proteins are incapable of causing disease. The types of subunit vaccines are
described in Table 1.

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Table 1: Types of subunit vaccines.

Type Description Examples

Protein-based Contain specific isolated proteins from Hepatitis B vaccine, acellular

vaccines viral or bacterial pathogens pertussis vaccine, human
papillomavirus vaccine

Polysaccharide- Contain chains of sugar-molecules Meningococcal polysaccharide

based vaccine (polysaccharides) found in the cell vaccine, pneumococcal
walls of some bacteria polysaccharide vaccine

Conjugated Contain combination of a weak antigen Pneumococcal conjugate vaccines,

vaccines with a strong antigen as a carrier haemophilus influenzae type b
conjugate vaccine, meningitis A
and B conjugate vaccines

Toxoid Vaccines: use a toxin (harmful product) made by the germ that causes a disease. They are
produced by purifying the toxin and altering it chemically usually with formaldehyde (e.g. tetanus
diphtheria (Td). While no longer toxic, the toxoid is still capable of inducing a specific immune
response protective against the effects of the toxin. That means the immune response is targeted
to the toxin instead of the whole germ. In some bacterial infections (e.g. diphtheria, tetanus), the
clinical manifestations of disease are caused not by the bacteria themselves but by the toxins they
secrete.

Viral vector-based vaccines: These vaccines are developed by introducing the genetic sequence
coding for the antigen from the pathogen into a viral vector that has been previously rendered non-
virulent by genetic techniques. Some viral-vector-based vaccines can replicate in the host cell
(replicating viral-vector vaccines), such as the recently approved Ebola vaccine and some vectors
do not replicate in the host cells (non-replicating viral vector vaccines) such as Janssen and
AstraZeneca Covid-19 vaccines, depending on modifications introduced into the vector genome.
the

Nucleic acid vaccines: use genetic material from a disease-causing virus or bacterium (a
pathogen) to stimulate an immune response against it. Depending on the vaccine, the genetic
material could be DNA or RNA; in both cases, it provides the instructions for making a specific
protein from the pathogen (gives your body instructions to make specific foreign proteins), which
the immune system will recognize as foreign (an antigen). Once, inserted into host cells, this

5
genetic material is read by the cell’s protein-making machinery and used to manufacture antigens,
which then trigger an immune response.

Messenger ribonucleic acid (mRNA) Vaccines: These vaccines are based on mRNA coding for
an antigenic protein that is generated in vitro and encased with suitable material (e.g., lipid-based
nanoparticle emulsion) that assures the delivery into the cell. The mRNA vaccines have several
benefits compared to other types of vaccines, including shorter manufacturing times and because
they do not contain a live virus, no risk of causing disease in the person getting vaccinated. These
vaccines have been shown to stimulate innate immunity. Therefore immune-mediated adverse
events are also possible with this type of vaccine. Residual molecules, originating from raw
materials, could induce unexpected immune responses.

Deoxyribonucleic acid (DNA) vaccines: use a gene from a virus or bacteria to stimulate the
immune system. The nucleic-acid segment is integrated into a bacterial plasmid carrier that
contains the encoding segment for the antigen, plus a promoter and other residual segments from
the virus or bacteria of origin. The potential for integration into host cell DNA poses a theoretical
risk; however, studies to date have shown that no retrovirus elements are available for their reverse
transcription into DNA.

2.1.2. Other components of vaccines

In addition to the primary antigen(s), vaccines also contain small quantities of other substances
which may cause AEFI. These include:

Adjuvants: a substance that is sometimes added to a vaccine to enhance the immune response by
degree and/or duration, making it possible to reduce the amount of immunogenic per dose or the
total number of doses needed to achieve immunity. The commonly used adjuvants are aluminium
salts (aluminium hydroxide, aluminium phosphate or potassium aluminium sulphate) which
primarily enhance the immune response to proteins. They have been shown to be safe over several
decades of use. Rarely, they may cause injection site reactions, including subcutaneous nodules,
sterile abscesses, granulomatous inflammation or contact hypersensitivity.

Antibiotics: are used during the manufacturing phase to prevent bacterial contamination of the
tissue culture cells in which the viruses are grown. For example, MMR vaccine and IPV each
contain less than 25 micrograms of neomycin per dose. Recipients who are known to be allergic
to neomycin should not be vaccinated with neomycin containing vaccine and be closely observed
if vaccinated unknowingly so that any allergic reaction can be treated immediately.

6
Preservatives: are chemicals (e.g. thiomersal, phenol derivatives) that are added to a killed or
subunit vaccines in order to inactivate viruses, detoxify bacterial toxins, and remain in the vial to
prevent serious secondary infections in multi-dose vials as a result of bacterial or fungal
contamination after they are opened.

Stabilizers: are compounds that may be added to vaccines for a variety of manufacture related
issues: controlling acidity (pH); stabilizing antigens through necessary steps in the manufacturing
process, such as freeze drying; and preventing antigens from adhering to the sides of glass vials
with a resultant loss in immunogenicity. Examples of such additives include potassium or sodium
salts, lactose, human serum albumin and a variety of animal proteins, such as gelatin and bovine
serum albumin.

2.1.3. Contraindications and precautions to vaccination

A contraindication to vaccination is a rare characteristic/condition in a recipient that increases the

risk of a serious adverse reaction if the vaccine is given. Ignoring contraindications can lead to
avoidable vaccine reactions. One of the most serious reactions following vaccination is
anaphylaxis which is the only contraindication applicable to subsequent doses of the same vaccine.
Most contraindications such as severe acute illnesses (e.g. acute respiratory tract infection) or
treatment with steroids are temporary and the vaccination can be administered later. These are
called temporary or relative contraindications. Precautions, in contrast, are events or conditions
that should be considered in determining if the benefits of the vaccine outweigh the risks
(especially if the recipient is immunocompromised or pregnant). Precautions stated in the product
labelling may sometimes be inappropriately interpreted as contraindications, resulting in missed
opportunities to vaccinate.

2.2. Adverse Events Following Immunization

An AEFI is any untoward medical occurrence (unfavourable or unintended sign, abnormal

laboratory finding, symptom, or disease) that follows immunization and that does not necessarily
have a causal relationship with the usage of the vaccine. Reported adverse events can either be true
adverse events i.e. resulting from the vaccine or immunization process or coincidental events that
are not due to the vaccine or immunization process but are temporally associated with
immunization. The five categories of AEFI as defined by the Council for International
Organizations of Medical Sciences (CIOMS) and WHO are described in the Table 2.

Table 2: Cause-specific type of AEFIs.

Cause-specific type of AEFI Definition

7
 Vaccine product-related reaction An AEFI is caused or precipitated by a vaccine due to one
or more of the inherent properties of the vaccine product.

Vaccine quality defect-related An AEFI that is caused or precipitated by a vaccine is due

reaction to one or more quality defects of the vaccine product,
including its administration device as provided by the
manufacturer.

Immunization error-related An AEFI that is caused by inappropriate vaccine handling,

reaction prescribing, or administration and thus by its nature is
preventable.

Immunization anxiety-related An AEFI arising from anxiety about the immunization.

reaction

Coincidental event An AEFI that is caused by something other than the vaccine
product, immunization error or immunization anxiety, but a
temporal association with immunization exists.

2.2.1. Vaccine Reactions

Vaccine reactions may be grouped into two broad categories: based on cause, and seriousness and
frequency.

a. Cause-specific vaccine reactions.

Vaccine product-related reaction: this is an individual’s reaction to the inherent properties of

the vaccine, even when the vaccine has been prepared, handled and administered correctly. Most
often the exact mechanism of a vaccine product-related reaction is poorly understood. The reaction
may be due to an idiosyncratic immune mediate reaction (e.g. anaphylaxis) or to replication of the
vaccine-associated microbial agent (e.g. vaccine-associated poliomyelitis following OPV which
contains attenuated live virus).

Vaccine quality defect-related reaction: this is due to a defect in a vaccine (or its administration
device) that occurred during the manufacturing process. Such a defect may have an impact on an
individual’s response and thus increase the risk of adverse vaccine reactions. Insufficient
inactivation of wild-type vaccine agents (e.g. wild polio virus) during the manufacturing process
or contamination introduced during the manufacturing process could cause vaccine quality defect-
related reactions.

8
 b. Vaccine reactions by seriousness and frequency

Most vaccine reactions are minor and subside on their own. Serious reactions are very rare and, in
general, do not result in death or long-term disability. Table 3 describes the frequency of
occurrence of reported adverse events.

Table 3: Frequency of occurrence of reported adverse reactions.

Frequency category Frequency in rate Frequency in %

Very common ≥ 1/10 ≥ 10%

Common (frequent) ≥ 1/100 and < 1/10 ≥ 1% and < 10%

Uncommon (infrequent) ≥ 1/1000 and < 1/100 ≥ 0.1% and < 1%

Rare ≥ 1/10 000 and <1/1000 ≥ 0.01% and < 0.1%

Very rare < 1/10 000 < 0.01%

Common or minor vaccine reactions are caused when the recipient’s immune system reacts to
antigens or the vaccine’s components (e.g. aluminium adjuvant, stabilizers or preservatives)
contained in the vaccine. Minor AEFIs could be local or systemic. Local reactions include pain,
swelling and redness at the injection site while systemic reactions include fever, irritability,
malaise, and etc. Some examples of the common and very common vaccine reactions are presented
in Table 4.

Table 4: Common and very common minor vaccine reactions by antigen type.

Fever
Vaccine Local adverse events Systemic symptoms
(> 380C)

BCG Injection site papule and mild - -

ulceration (in almost all vaccinees)

Hepatitis B Injection site pain (3-29%) 1 – 6% Headache (3%)

Injection site pain (3%)

Erythema (3%)

Hib Injection site reaction (10%) 2-10% Irritability (35-71%

Measles Injection site reaction (17-30%) 5-15% Rash (2-5%)

OPV - 11.7% Abdominal pain (17.2%)

9
 Headache (22.4%)

Diarrhoea (9.9%)

Asthenia (7,5%)

GI* (33.5%)

Nervous system (29.3%)

DPT Local redness (37.4%) 31.5% Drowsiness (31.5%)

Swelling (40.7%) Anorexia (20.9%)
Injection site pain (50.9%) Vomiting (6.2%)
Fretfulness (53.4%)
Td Local reaction (38%) ~ 10% Malaise (3-10%)
Injection site pain (20% Headache (3-10%)
Fever (3-10%)
HPV Injection site pain (83%) 13% Urticaria (3%)
Swelling (25%) Headache (26%)
Myalgia (2%)
Arthralgia (1%)
Gastrointestinal disorders
(17%)
PCV13 Injection site swelling (25%) 33.3% Drowsiness (50%)
Injection site tenderness (25%)
Injection site swelling (25%)
Covid-19 Injection site pain (80-89%) 10-16% Irritability (70-83%)
vaccine Injection site swelling (80-89%) Malaise (70-83%)
(Pfizer Injection site redness (80-89%)
BioNTech)

Rotarix - 1.9 per -

1000

Rabies Injection site pain (60-89.5%) Fever (7-55.6%)

(Human Injection site swelling (60-89.5%) Headache (7-55.6%)
Diploid Cell) Injection site induration (60-89.5%) Dizziness (7-55.6%)
Vaccine GI* (7-55.6%)

10
 Meningitis A Injection site pain (0.36%) 1.87% Headache (0.66%)
Injection site swelling (0.05%) Myalgia (0.15%)
Injection site abscess (0.03%) Asthenia (0.06%)
General pruritus (0.26%)
Yellow fever Injection site pain/tenderness (14%) 8.3% Nausea (5.5%)
vaccine Injection site erythema (1.3%) Vomiting (1.4%)
Injection site haematoma (1.9%) Myalgia (12.8%)
Injection site induration (1.4%) Arthralgia (7.5%)
Injection site swelling (1.0%) Headache (18%)
Asthenia (16.6%)

Oral Cholera - - Headache (10%)

vaccine Abdominal pain (10%)

Tiredness (10%)

Vomiting (10%)

Loss of appetite (10%)

Hepatitis B Injection site pain- (3-29%) 1-6% Headache (3%)

birth dose Erythema (3%)

Injection site swelling (3%)

*Gastrointestinal symptoms other than mentioned in the table.

Rare or serious vaccine reactions are caused by the body’s reaction to a particular component in a
vaccine. AEFIs are considered serious by definition if they:

• result in death
• are life-threatening.
• require in-patient hospitalization or prolongation of existing hospitalization.
• result in persistent or significant disability/incapacity
• result in a congenital anomaly/birth defect
• other medically important conditions

The rate of occurrence of some of the rare and more serious reactions has been summarized in the
Table 5 on the next page

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Table 5: Serious vaccine reactions, onset interval and frequency.

Rate per million

Vaccine Reaction Onset Interval
(1,000,000) doses
Suppurative lymphadenitis 2-6 months 100-1000
BCG BCG osteitis 1-12 months 1 -700
Disseminated BCG infection 1-12 months ~ 1-2
Hepatitis B Anaphylaxis 0 – 1 hour 1–2
Febrile seizures 6-12 days 330
Thrombocytopenia 15-35 days 30
Measles/MMR/MR
Anaphylaxis 0-1 hour ~1
Encephalopathy 6-12 days <1
Vaccine associated paralytic 4-30 days 0.4 – 3
Oral poliomyelitis
poliomyelitis (VAPP)
Tetanus Toxoid, Brachial neuritis 2-28 days 5-10
DT Anaphylaxis 0-1 hour 1–6
Persistent (>3 hours) inconsolable 0-24 hours 1000-6000
screaming
Pertussis (DTwP)
Seizures 0-3 days 80-570
Hypotonic, hypo-responsive episode 0-48 hours 30-990
(HHE)
Anaphylaxis 0-1 hour 20
Encephalopathy 0-2 days 0-1
Rotarix Intussusception 0-21 days 0.1 after first dose
Human Papilloma Anaphylaxis 0-2 hours 1.7-2.6
Virus (HPV)
Vaccine
Thrombosis with thrombocytopenia Within 4-28 days
COVID 19-vaccine
syndrome (TTS) 21 days after
(AstraZeneca
Guillain-Barre syndrome vaccination
/Covishield)

COVID 19-vaccine Guillain –Barre syndrome 42 days

Janssen and following
Janssen Blood clotting disorders vaccination.

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 Rate per million
Vaccine Reaction Onset Interval
(1,000,000) doses
Within 21 days
Cerebral venous sinus thrombosis people under the
(CVST) age of 60

Notes:

• Reactions (except anaphylaxis) do not occur if already immune (~90% of those receiving a
second dose are immune): children over six years unlikely to have febrile seizures.
• VAPP Risk is higher following the first dose (1 in 750,000 compared to 1 in 5.1 million for
subsequent doses) and for adults and immune-compromised.
• Seizures are mostly febrile, and the risk depends on age, with much lower risk in infants under
the age of 4 months.

2.2.2. Immunization error-related reactions

An adverse event can occur as a result of inappropriate handling, prescribing or administration of

a vaccine (Table 6). It is very important to identify and correct these errors as they are preventable
(otherwise they may derail the benefits of the immunization program. An immunization error-
related reaction may lead to a cluster of events associated with immunization. These clusters are
usually associated with a particular provider, health facility, or even a single vial of vaccine that
has been inappropriately prepared or contaminated. Immunization error-related reactions can also
affect many vials. For example, freezing the vaccine during transport may lead to an increase in
local reactions.

Table 6:Immunization error-related reactions.

Immunization
Examples Related reaction
error

Exposure to excess heat or Systemic or local reactions due to changes

Error in vaccine
cold as a result of in the physical nature of the vaccine, such
handling
inappropriate transport, as agglutination of aluminium-based
storage or handling of the excipients in freeze-sensitive vaccines

13
 Immunization
Examples Related reaction
error

vaccine (and its diluents

where applicable)

Use of a product after the Failure to protect as a result of loss of

expiry date potency or no viability of an attenuated
product

Failure to adhere to a Anaphylaxis, disseminated infection with

Error in vaccine
contraindication a LAV e.g. Disseminated BCG
prescribing or non-
Failure to adhere to vaccine Systemic and/or local reactions,
adherence to
indications or prescription neurological, muscular, vascular or bone
recommendations
(dose or schedule) injury due to incorrect injection site,
for use
equipment or technique

Use of an incorrect diluent or Failure to vaccinate due to incorrect

injection of a product other diluent, reaction due to inherent properties
than the intended vaccine of whatever was administered other than
Error in
the intended vaccine or diluent
administration
Incorrect sterile technique or Infection at/beyond the site of injection
inappropriate procedure with
a multidose vial

2.2.3. Immunization anxiety-related reactions

Individuals and groups can become stressed and may react in anticipation to, and as a result of,
any kind of injection. This reaction is unrelated to the constituents of the vaccine product. Fainting
(vasovagal syncope or syncope) is relatively common, particularly in children over five years of
age and among adolescents. Some children who faint may have a syncopal hypoxic convulsion.
Younger children may have breath-holding and vomiting as a common symptom of anxiety. They
may also scream or run away to avoid the injection. Some individuals may have needle-phobia.

In group immunization/ mass campaign, mass hysteria is possible, especially if one or more of the
vaccine recipients are observed by others to faint or have some other reaction such as itching,
weakness of limbs and so on. Hyperventilation as a result of anxiety about the immunization leads

14
to specific symptoms such as light-headedness, dizziness, and tingling around the mouth and in
the hands.

2.2.4. Coincidental events

An event may occur coincidentally with immunization and sometimes be falsely attributed to the
vaccine i.e. a chance temporal association is falsely attributed to immunization. Such temporal
associations are inevitable, especially during a mass immunization campaign.

Vaccines are normally administered early in life when infections and other illnesses including
manifestations of underlying congenital or neurological conditions are common. It is, therefore,
possible to encounter many events, including deaths that can be falsely attributed to vaccines
through a chance association. For example, the incidence of sudden infant death syndrome (SIDS
or “cot death”) peaks around the age of early childhood immunization. Consequently, many SIDS
cases will occur in children who have recently been immunized. However, several well-designed
studies have shown that the association of SIDS and immunization is coincidental and not causal.

Coincidental adverse events may be predictable. The number of events to be expected depends
upon the size of the population and the incidence of disease or death in the community. Knowledge
of these background rates of disease and deaths, particularly age-specific disease incidence rates,
allows estimation of the expected numbers of coincidental events.

15
3. Prevention and management of AEFI

Vaccines used in the national immunization program are relatively safe and effective. There may
be predictable adverse reactions of which most are mild and resolve quickly. However, it is not
always possible to predict individuals who might have a mild or serious reaction to a vaccine.

3.1. General principles of prevention and management of AEFI

• Vaccines are very rarely contraindicated. However, it is important to check for

contraindications to avoid serious reactions. For example, a vaccine is contraindicated if there
is a history of anaphylaxis to a given vaccine or its components in previous vaccinations.
• The proposed waiting time of 15-30 minutes at the health facility will allow the identification
and immediate management of medical emergencies like anaphylaxis which manifests most
frequently within 5 to 30 minutes of vaccine administration.
• Vaccine anaphylaxis is very rare. However, it is recommended that preparedness to provide
emergency treatment for anaphylaxis is necessary in all health facilities. All immunization
providers need to be trained and develop competence in recognizing and managing anaphylaxis
and have epinephrine (adrenaline) available.
• For parents, advice should be given on managing the common minor reactions, in addition to
instructions on seeking proper medical care if there are more serious symptoms. Such action
will help to reassure parents about immunization and prepare them for common reactions and
to adhere to subsequent vaccination schedules as well.
• Antipyretic drugs, in a recommended dosage and schedule, can be given as recommended by
the prescriber (or manufacturer). For example, paracetamol, at a dose of up to 15 mg per kg
every 6-8 hours with a maximum of four doses in 24 hours, is useful for common minor
reactions; it eases pain and reduces fever. However, it is important to advice against overuse
of paracetamol or any other antipyretic drug as overdosing may harm the vaccine recipients.
A febrile child can be cooled with a tepid sponging or bath, and by wearing light cool clothing.
Extra fluids need to be given to children with fever. For a local reaction, a cold cloth applied
to the site may ease the pain.
• Using local remedies for any serious vaccine reaction can risk the health and life of the
recipients and is strongly discouraged. Early medical care by a qualified clinician will
minimize any unwanted outcome and ensure early recovery and may also save lives.

3.2. Prevention and management of immunization error-related reactions

As mentioned in the previous chapter, immunization error-related reactions are preventable, and
identification and correction of these errors in a timely manner are important. Prior to the

16
introduction of auto-disable (AD) syringes, the most common immunization error was an infection
as a result of a non-sterile injection and contamination of the vaccine or diluents vial or the
injecting device (syringe and/or needle). The infection could manifest as a local reaction (e.g.
suppuration, abscess) or a severe systemic reaction (e.g. sepsis, toxic shock syndrome). In addition,
there was the perception of a risk linking immunization with blood borne infections. Nevertheless,
one needs to consider infection can occur in cases of mass vaccination or in disaster situations,
particularly if there is a shortage of supplies or problems with logistics. This can be avoided by
proper planning and preparedness of program managers.

The symptoms arising from an immunization error may help to identify the likely cause. For
instance, children immunized with contaminated vaccine (usually the bacterium Staphylococcus
aureus) become sick within a few hours with an injection site reaction (local tenderness, redness
and swelling) and then develop systemic symptoms (vomiting, diarrhoea, high temperature, rigors
and circulatory collapse). Bacteriological examination of the vial, if still available, can confirm the
source and type of infection.

Sterile abscesses, while rare (~1 per 100 000 doses) are local reactions from aluminum-containing
vaccines, especially DTP. They, along with other local reactions, are more likely to occur if there
is inadequate shaking of the vaccine before use, superficial injection and use of a vaccine that had
been frozen. Contamination of vaccine or injection equipment can lead to a bacterial abscess. For
BCG vaccine, injection abscess can result from improper technique of injection (subcutaneous
rather than intradermal injection).

Ignoring contraindications may lead to serious vaccine reactions and is considered an

immunization error. The immunization team should be aware of such contraindications and any
precautions. Any uncertainty should be referred to a higher level – a program manager,
paediatrician or physician. However, it is equally important not to overreact to concerns of false
contraindications as this may lead to missed opportunities for vaccination, reducing coverage and
thereby increasing the risk of disease in both individuals and the community.

Healthcare providers also need a clear understanding of contraindications and precautions. As

mentioned in the previous chapter, precautions are not contraindications, but a decision on whether
to vaccinate requires a case-based assessment where the risk of the vaccine is balanced against the
potential benefits. The use of live vaccines in pregnancy is a good example of this.

To avoid/minimize immunization error, the following should be observed.

• It is both important and necessary to maintain the cold chain at all levels.
• Vaccines must be reconstituted only with the diluents supplied by the manufacturer.

17
• Reconstituted vaccine should be maintained in the recommended cold chain and used within
six hours after reconstitution; it must be discarded at the end of each immunization session and
should never be retained.
• Other than vaccines, no other drugs or substances should be stored in the refrigerator of the
immunization centre.
• Immunization workers must be adequately trained and closely supervised to ensure that proper
procedures are followed.
• Careful epidemiological investigation of an AEFI is needed to pinpoint the cause and to correct
immunization practices.
• Prior to immunization, adequate attention must be given to contraindications.

Follow-up and corrective actions following immunization error-related reactions should be based
on the findings of the investigation. Depending on the nature of the immunization error, these
actions can be both general (e.g. training and awareness) and specific (e.g. strengthening cold chain
maintenance if the problem is found to be related to cold chain issues). Continued monitoring and
supportive supervision can help to minimize these adverse events.

3.3. Prevention and management of immunization anxiety-related reactions

Training and awareness to enable health professionals/staff to identify and manage medical
emergencies appropriately is important. Fainting does not require any clinical management
beyond placing the patient in a recumbent position. Syncopal hypoxic convulsions are short-lived
generalized tonic-clonic seizures which can be managed by keeping the child lying down and
securing the airway by placing the child on one side to prevent aspiration should the child vomit.
The seizure will end spontaneously but, if prolonged or focal, further investigations may be
required.

The likelihood of fainting should be anticipated when immunizing older children. It can be reduced
by minimizing stress among those awaiting injection, through short waiting times, comfortable
room temperatures, preparation of the vaccine outside the recipient’s line of vision, and privacy
during the procedure.

Sometime, cases with hysteria may even require hospitalization and can cause public concern.
Clear explanations about the immunization and a calm, confident delivery will decrease the level
of anxiety about the injections and thus reduce the likelihood of an occurrence.

Sometimes a fainting episode can be misdiagnosed as anaphylaxis. Careful observation and

clinical judgments are necessary to differentiate. However, an accidental administration of a single
dose of adrenaline (intramuscularly) to a vaccine recipient with only syncope does not harm the

18
vaccine recipient. Besides, it is necessary to promote training and awareness to enable health staff
to identify and manage medical emergencies appropriately.

3.4. Management of suspected anaphylaxis or collapse after vaccination

Sudden and severe events occurring post-vaccination, especially syncope, are frequently reported
as anaphylaxis. However, anaphylaxis following vaccination is very rare and the risk (in general)
is 1.3 episodes per million doses of vaccine administered. The onset of anaphylaxis can occur after
several minutes (> 5 minutes) but rarely up to two hours following vaccination. The progression
of symptoms is rapid and usually involves multiple body systems, almost always with skin
involvement (generalized erythema and/or urticaria) as well as signs of upper and/or lower
respiratory tract obstruction and/or circulatory collapse. In young children (though anaphylaxis
occurs at any age) limpness, pallor or loss of consciousness may reflect hypotension. In general,
the more rapid the onset, the more severe the reaction. For all cases of suspected anaphylaxis, all
symptoms and signs must be well documented by health-care providers. Because anaphylaxis is
very rare, other causes of sudden and severe symptoms post-immunization that are more common
than anaphylaxis need to be considered (Table 7).

Table 7: Conditions that may be mistaken for anaphylaxis post-immunization.

Diagnosis Onset: symptoms and signs

Vasovagal event Symptoms are usually immediate (< 5 minutes) and commence
during the injection process. No skin rash, bradycardia not
tachycardia, no respiratory involvement, spontaneous
resolution when prone.

Hypotonic hypo-responsive Onset 2-6 hours post-immunization, sudden pallor, hypotonia

episode and unresponsiveness, usually in an infant. No skin rash, or
respiratory or cardiovascular compromise.

Seizure Onset usually at least 6-8 hours post-vaccination with a killed

vaccine. Sudden unresponsiveness usually with tonic-clonic
movement, usually febrile, no cardiovascular compromise, no
respiratory compromise unless apnoea or aspiration.

Aspiration of oral vaccine (e.g. Immediate respiratory symptoms (cough, gagging, stridor or
OPV or Rota virus vaccine) wheeze) during administration, usually in infants. No skin rash
or cardiovascular compromise.

19
 Somatic conversion symptoms Immediate or delayed respiratory symptoms, syncope,
neurological symptoms without objective respiratory or
neurological signs.

Severe coincidental diseases Usually due to coincidental unrecognized congenital heart

disease or occult infections. May have respiratory or
cardiovascular compromise but there are usually symptoms,
signs or investigations to indicate alternate causes.

Immunization- error related Immediate toxic drug reaction with symptoms and signs due to
drug toxicity. Reported with immunization related errors which
have resulted from inadvertent administration of a muscle
relaxant or insulin.

Emergency equipment must be immediately at hand whenever immunizations are given. Each
vaccinator must have an emergency kit with adrenaline (see box on the next page) and be familiar
with its dosage and administration (Table 8). The expiry date of the adrenaline should be written
on the outside of the emergency kit and the whole kit should be checked three- or four-times a
year. Adrenaline that has a brown tinge must be discarded. All vaccinators must be familiar with
the practical steps necessary to save lives following anaphylaxis.

Table 8:Adrenaline dosing and administration for treatment of anaphylaxis.

Drug, site, and route Frequency of administration Dose

of administration

Adrenaline Repeat every 5-15 minutes as Children: 0.01mg/kg

(epinephrine) needed until there is a resolution Adults: 0.2 mL to a maximum of 0.5
1:1000 of the anaphylaxis. mL
Immediate IM injection If weight is unknown,
to the midpoint of the Note: Persisting or worsening
• Less than 2 years: 0.0625 ml
anterolateral aspect of
cough associated with pulmonary (1/16)
the middle third of the oedema is an important sign of
• 2-5 years: 0.125 ml (1/8)
thigh adrenaline overdose and toxicity • 6-11 years: 0.25 ml (1/4)

20
 • Over 11 years: 0.5 ml (1/2)

Note: Anaphylaxis can also be caused by agents other than vaccines (e.g., drugs).

Contents of an AEFI treatment kit

• Injection adrenaline (1:1000) solution –at least 2 ampoules
• Disposable syringe (insulin type) having mL graduations and IM needle (gauges and
length adjusted to targeted recipients) – sets.
• Scalp vein set – 2 sets with medium-bore needles (gauges and length to be adjusted to
targeted recipients)
• IV cannula (various sizes, adjusted to targeted recipients)
• Paracetamol (500 mg) – 10 tabs
• IV fluids (Ringer’s lactate or normal saline) - 1 unit in plastic bottle
• IV fluid therapy – 1 unit in plastic bottle
• IV drip set – 1 set
• Cotton wool + adhesive tape – 1 each
• AEFI reporting forms.
• Label showing date of inspection, expiry date of injectable adrenaline and shortest
expiry date of any of the components.
• Drug dosage tables for injecting adrenaline
• At hospital, oxygen support and airway
• Intubation facility should be available.
.

4. Adverse Events Following Immunization Surveillance System in Ethiopia

The implementation of AEFI surveillance system is a collaborative action among different

stakeholders. AEFI surveillance is an integral part of the national pharmacovigilance activities. It
reinforces the safe use of vaccines in the country while helping to maintain public confidence in
the immunization program. In Ethiopia, active, spontaneous and stimulated passive surveillance
systems are commonly implemented to monitor vaccine safety. AEFI surveillance starts with
identification of AEFIs. The identified AEFIs will be notified to the responsible body in the
healthcare systems and then be reported to the next level following appropriate channels of
reporting. The collected AEFIs will be analysed and for eligible AEFIs, investigation and causality
assessment are performed. Finally, based on the findings, corrective action can be taken, and
feedback will be communicated to the relevant stakeholders (Fig. 1).

21
Figure 1: AEFI Surveillance Cycle

4.1. Objectives of AEFI Surveillance System

The major goal of AEFI surveillance is early detection and analysis of adverse events and
providing appropriate and quick response in order to decrease the negative impact on the health of
individuals and the immunization programme thereby enhancing program credibility and
providing country-specific data on vaccine safety. The specific objective of AEFI surveillance is
to:

• Quickly detect and respond to any adverse event following vaccination.

• Closely monitor the safety of newly licensed and/or introduced vaccines.

• Detect previously unrecognized reactions of both existing and newly licensed/introduced

vaccines.

• Estimate rates of occurrence of AEFIs in the local Ethiopian population compared with clinical
trial and international data.

• Detect apparent increases or decreases in the rates of previously reported events.

• Prevent false blame arising from coincidental AEFI, which may have a known or unknown
cause unrelated to immunization.

22
• Identify vaccine lots or brands leading to unusual number and types of vaccine reactions caused
by the inherent properties of a vaccine.

• Detect, correct and prevent immunization error-related AEFIs.

• Maintain confidence by properly responding to parent/community/stakeholders’ concerns,

while increasing awareness (public and professional) about vaccine risk

• Generate new hypotheses about vaccine reactions specific to defined populations in Ethiopia.

• Detect pre-existing conditions that may promote reactions and may represent contraindications
or precautions to additional doses.

• Trigger further clinical, epidemiologic, or laboratory investigations regarding a possible causal

relationship between a vaccine and the adverse event.

• Share vaccine safety information to the global community to support generation of new and
additional information on vaccine safety/signal detection.

4.2. Types of AEFI Surveillance System

There are mainly two types of AEFI surveillance systems: passive and active surveillance. In
addition, stimulated passive surveillance can also be used.

Passive surveillance: This encompasses all spontaneous AEFI reporting from immunization
service providers/healthcare facilities/clients/patients to the first administrative level in the
surveillance system. Passive surveillance systems theoretically allow anyone in a country to report
and due to their broad coverage, they can provide the first indication of an unexpected AEFI.
Therefore, the main strength of passive surveillance is to detect early the unknown serious AEFI
(signals). However, passive surveillance has many limitations, including underreporting. Thus,
passive surveillance is often not useful for determining whether the rate of an adverse event has
increased. Thus, newly introduced vaccines and/or special immunization campaigns should have
added layers of active surveillance and/or epidemiological studies to maximize the effectiveness
of passive AEFI surveillance (e.g. enhanced spontaneous surveillance introduced during special
immunization campaigns to encourage reporting by service providers or receivers).

Active surveillance: Active (proactive) AEFI surveillance is an active system for the detection of
adverse events. This is achieved by active follow-up after vaccination. Events can be detected by
asking vaccinees directly or by screening their records. It is best done prospectively. This is
primarily used for characterization of the AEFI profile, rates and risk factors, but logistical and
resource constraints limit its wide application. Active AEFI surveillance may be carried out only

23
for selected AEFI or vaccines at selected institutions (sentinel sites). It can also be carried out in
the community setting (e.g. cohort event monitoring).

4.3. AEFI Detection and Reporting

All AEFIs brought to the notice of health professionals or detected by them should be reported to
the next level using the standard AEFI reporting tools.

4.3.1. Components of AEFI Reporting

[Link]. What to report?

All AEFIs including minor AEFIs, serious AEFIs, events with an unexpected high rate or unusual
severity, signals, significant events of unexplained cause after vaccination, events causing
significant parental/family/health professional/community concerns, potential immunization
errors and adverse events of special interest (AESIs).

[Link]. When to report?

A report must be made as quickly as possible so that an immediate decision can be made on the
need for action and investigation. Serious AEFIs, AEFIs as a result of potential immunization
errors, clusters of AEFIs, AEFI causing parental or community concern, AEFIs that are known but
occur with unexpected frequency and potential signals (unknown/unexpected AEFI) should be
reported to EFDA immediately. In case of serious AEFI, vaccine administrators should notify their
supervisors and/or woreda immunization officers immediately within 24 hours (over telephone)
and send the completed reporting form to EFDA within 48 hours. In case of minor AEFIs,
individual case safety reports should be line-listed and sent to the next higher level at least on a
monthly basis.

[Link]. Who should report?

All health professionals including nurses, physicians, pharmacists, midwives, public health
officers and laboratory technologists.

[Link]. How to report?

Health professionals should report AEFIs using appropriate reporting tools. However, serious
adverse evets (SAE) should be reported using standard AEFI reporting yellow form. Commonly
utilized AEFI reporting tools include:

Paper-based reporting tools: paper-based (manual) AEFI reporting format (Annex I) can be used
to report any suspected individual case safety report (ICSR). The completed ICSR can be delivered

24
to the responsible body in person, through pre-paid mail ([Link] 5681) or through emailing of
scanned copy to EFDA’s email address pharmacovigilance@[Link].

Electronic reporting tools: health professionals can use electronic reporting tools to report any
AEFIs. The electronic reporting tools include Med Safety mobile application and e-reporting
system through EFDA’s website ([Link]).

Toll Free line: The authority has a toll-free call line (8482) for notifying/reporting an AEFI by
health professionals, vaccine recipients and care givers as well.

It is important that all of the minimum required information is entered into the reporting form, as
this is the basis for decisions regarding the need for further investigation. WHO recommended 22
core variables, with 10 identified as critical (minimum information) that should be collected for
any AEFI surveillance (Table 9).

Table 9: Core variables: minimum information required for reporting in AEFI surveillance.

Category Core variable

Date AEFI report first received at national

Identity Centre *Location (address)

Country where this AEFI was reported

*Patient identifier Sex

*Date of birth (or) age at time of onset (or)

Case
age *Medical history
group at onset

*Primary suspect vaccine name (generic) *Batch number and expiry date

Vaccine Other vaccines given just prior to AEFI. Vaccine dose number for this

particular vaccine

*Date and time of vaccination *Adverse event

Event
*Date and time of AEFI onset *Outcome of AEFI

Reporter Name of first reporter of AEFI Email

Institution/location
Telephone number
Profession/department

25
 Comments (if any) by national officer before the report is uploaded to the Global
Other
Database

*The ten critical (mandatory) core variables

4.3.2. Reporting AEFIs during immunization campaigns

A campaign is an opportunity to strengthen or establish immunization safety surveillance. Proper

planning to reduce immunization error-related reactions, to monitor and respond to AEFI can
minimize adverse events and their effects during a campaign. Careful planning will limit the
potential for negative publicity from an AEFI. During mass immunization or a special
immunization programme, it is of utmost importance to ensure AEFI reporting for two reasons:

• Mass immunization and special immunization programmes cover a large number of individuals
in a particular target group in a specified time period. Therefore, an excess number of adverse
events may be reported within a short time period. The rate of events remains unchanged, but
the increased number of events tends to be noticed by both staff and the public, particularly
when injectable vaccines are used and at a time of high social mobilization. Unless an event is
properly investigated or analysed, it can cause concern among the public and also may affect
the immunization programme.
• During special immunization programmes, a new vaccine may be introduced with no prior
experience of, or little information on, adverse reactions. There is a possibility of detection of
signals through strengthening surveillance during special immunization programmes.

[Link]. To whom to report?

Health professionals complete and submits an AEFI form to the health facility’s EPI Coordinator.
The report is then submitted to the next higher administrative level and finally all the reports should
be submitted to EFDA as shown in the diagram below (Fig. 2).

26
 AEFI Reporting Route, Timeline and Actions

Health Facility Health Facilities

WoHO and ZHD • Health posts send AEFI reports to
• Receive and check quality of health centres (HC)
AEFI line-list. • HCs and District Hospitals send AEFI
• Compile AEFI line-list and reports to WoHO
send it to next level monthly. • General hospitals send AEFI reports to
• Provide feedback to the lower ZHD.
levels. • Complete ICSR for each vaccinee
Woreda Health
• Compile ICSR into standardized AEFI
Office (WoHO) line-list or feed into DHIS2.
• Send compiled AEFI line list monthly
to WoHO.
• In case of serous AEFI, send the report
to WoHO and EFDA within 48 hours.
Zonal Health
Department
(ZHD)

EFDA
RHB/ Regulatory Body • Receive and check quality of AEFI
• Receive and check quality line-list.
of AEFI line-list. Regional Health • Share AEFI data to the global
• Compile AEFI line-list and Bureau (RHB)/ community.
send it to EFDA monthly. Regulatory Body • Select AEFI cases for investigation.
• Initiate AEFI investigation • Ensure initiation of AEFI
within 15-days of
investigation within 15 days
notification
• Conduct AEFI investigation when
• Provide feedback.
needed.
• Organize conduction of causality
MOH assessment
• Promote AEFI reporting • Manage AEFI Data
EFDA
via DHIS2 and another • Provide feedback.
existing tool. • Take regulatory measure if
• Ensure proper AEFI case necessary.
management.
• Use and cascade feedback
provided by EFDA.
• Provide feedback to lower
Key:
level. Report
MOH Feedback

27
4.4. Investigating AEFIs

Investigation of an AEFI report is critical to identify and correct the problem(s)as well as to ensure
trust among clients and different Expanded Programme on Immunization (EPI) actors. During an
investigation, evidence, information, and documents will be collected for further action. The goal
of an investigation is to collect further information about the cases for causality assessment.

The most important pre-requisite of an AEFI case investigation is to frame a diagnosis of the case
based on history, clinical examination, study of documents and reports and field visit. The findings
of the investigation may lead to appropriate action and prevent further AEFIs. Investigation should
identify any immunization related errors because these are preventable. If co-incidental events are
recognized, proving them will be important to maintain public confidence in the immunization
program.

4.4.1. Objectives of AEFI investigation

The goal of an AEFI investigation is to search for detailed information of an adverse event and
take appropriate corrective actions when necessary to maintain public confidence in the
immunization program. The specific objective of an AEFI investigation is to:

• Confirm the reported diagnosis or establish a diagnosis.

• Document the outcome of the reported adverse event.

• Identify the details of vaccine (s) administered and to determine the timing between
administration of the vaccine and the onset of the event.

• Examine the operational aspects of the program. Even if an event seems to be vaccine induced
or coincidental, immunization related errors may have increased its severity.

• Determine whether a reported event was a single incident or one of a cluster and if it is a cluster
where the suspected immunizations were given and what vaccines were used.

• Determine whether similar events are occurring in individuals who have not received the same
vaccine.

• Address parent/community concerns.

• Generate new hypotheses about vaccine reactions that are specific to the population.

• Identify the cause of AEFI if possible.

4.4.2. What should be investigated?

The following medical incidents, i.e., trigger events, should be investigated.

28
• All serious AEFI cases

• Clusters and events above the expected rate and severity

• Suspected signals/previously unrecognized event associated with an existing or newly

introduced vaccines.

• Suspected immunization error

• Significant events of unexplained cause within plausible time of vaccination

• Events causing significant parental and community concerns AEFI that appears on the list of
events defined for AEFI surveillance.

• Any unexpected adverse event following vaccination should be reported and investigated
irrespective of the time interval between vaccination and onset of symptoms.

4.4.3. Who should be involved in AEFI investigation?

AEFI investigation taskforce is established in each region which is composed of representatives

from regional EPI, regulatory body, Public Health emergency management, pharmacy service,
EFDA branch office. The AEFI investigation taskforce is responsible to conduct AEFI case
investigation in their respective regions. EFDA, national PV advisory committee, National EPI
and development partners will provide support as needed. When there is a gap for an investigation
to be conducted by the regional AEFI investigation taskforce, team of experts from the national
level will conduct the investigation.

4.4.4. When to investigate?

The urgency of the investigation will depend on the situation. However, investigation should begin
within fifteen days of notification to the EFDA. Early AEFI case investigation helps to identify
any possible immunization error(s) that might be present and correct them before other people are
exposed to the same error, and to show members of the community that their health concerns are
taken seriously.

4.4.5. How to investigate?

Every preparation that needs to be done should be done before beginning data collection.
Furthermore, it is important to notify all parties involved. An AEFI investigation follows standard
epidemiological investigation principles. In addition, investigation of the vaccine(s),
administration techniques and procedures, and service in action should be conducted. All
necessary data should be collected during AEFI investigation by using standard AEFI investigation
form (Annex II). The investigation task force should:

29
• Obtain information from patient or relatives directly/ use available records.
• Obtain information from immunization service providers and medical care service providers
(hospital staff)/ use available records.
• Ask about the vaccine(s) administered and other drugs potentially received.
• Establish a more specific case definition if needed.
• Ask about other vaccines who may have received the same or other vaccines.
• Observe the service in action.
• Ask about cases in unvaccinated persons.
• Formulate a hypothesis as to what may have caused the AEFI.
• Collect specimens (if indicated by investigation, but not as a routine):
o from the patient
o the vaccine and diluent if applicable
o the syringes and needles
• Dispatch specimens to appropriate testing facility (laboratory, regulatory authority, etc.)

It is important to investigate suspected adverse events promptly and completely. During the
investigation process, the investigation team should communicate with all concerned parties on
process of investigation without suggesting the cause. The investigation task force should follow
the following steps while conducting the investigation (Table 10).

Table 10: Steps of AEFI Investigation and actions taken at each step.

Steps Actions

1) Confirm • Obtain patient’s medical file (or other clinical record)

information in • Check details about patient and event from medical file and document
report information.
• Obtain any details missing from AEFI Report Form.
• Identify any other cases that need to be included in the investigation

2) Investigate • Immunization history

and collect data: • Previous medical history, including prior history of similar reaction or other

About the allergies.

patient: • Family history of similar events

• History, clinical description, any relevant laboratory results about the AEFI
and diagnosis of the event

30
 • Treatment, whether hospitalized, and outcome

• Conditions under which the vaccine was shipped, its present storage condition,
About the event: state of vaccine vial monitor, and temperature record of refrigerator.
• Storage of vaccine before it arrived at health facility, where it has come from
higher up the cold chain, vaccine monitor card.
About the
suspected • Whether others received the same vaccine and developed illness

vaccine(s): • Whether others had similar illness (may need case definition); if so exposure
of cases to suspect vaccine(s)
About other
• Investigate the local immunization service
people:

3) Assess the • Vaccine storage (including open vials), distribution, and disposal.
service by: • Diluent storage and distribution
• Reconstitution (process and time kept)
• Use and sterilization of syringes and needles.
Asking about:
• Details of training in immunization practice, supervision and vaccinator(s)
• Number of immunizations greater than normal?

• Refrigerator-what else is stored (note if similar containers stored next to

Observing the vaccine vials which could be confused); which vaccines/diluents stored with
service in other drugs; whether any vials have lost their label.
action: • Immunization procedures (reconstitution, drawing up vaccine, injection
technique, safety of needles and syringes; disposal of opened vials)
• Do any open vials look contaminated?

4) Formulate a • On the likely/possible cause(s) of the event.

working
hypothesis

5)Test working • Does case distribution match work hypothesis?

hypothesis • Occasionally, laboratory tests may help.
• If program related errors are working hypothesis, correct them.
• Vaccine problems suspected, quarantine suspect vaccines

6)Conclude • Reach a conclusion on the cause/propose the possible cause.

investigation • Complete AEFI Investigation Form

31
 • Take corrective action, and recommend further action

4.4.6. Investigation of AEFI with fatal outcome

In the event of an identified death following immunization, the field investigation has to be
initiated immediately. All administrative levels including the national immunization program
should be notified of the death. As any fatality temporally linked to a vaccination can cause panic,
the public will also demand an immediate explanation thus an investigation has to be conducted
without any delay. A postmortem examination(autopsy)is preferred and recommended following
all deaths suspected to be caused by a vaccine / immunization. However, the decision to conduct
a post-mortem should be within the religious, cultural acceptance and legal framework of the
country. If autopsy is not possible verbal autopsy can be carried out.

4.4.7. Investigating AEFI clusters

A cluster of AEFI is defined as two or more cases of the same adverse event related in time, place
or vaccine administered. Apart from checking on these three factors, the investigators should look
for AEFI occurring in similar age groups and populations with genetic predisposition or disease.
Cluster investigation begins by establishing a case definition for the AEFI and related
circumstances and by identifying all cases that meet the case definition. The investigators should
demarcate the cluster and identify common exposure factors within the cluster. Cluster
identification (i.e. cases with common characteristics) are done by gathering details (Who, when
and where) of vaccines administered. This can be achieved by collecting and recording:

• Detailed data on each patient.

• Program-related data (storage and handling, etc.); and
• Immunization practices and the relevant health professionals’ practices.

Common exposures among the cases can be identified by reviewing:

• All data on vaccine(s) used (name, lot number, etc.).

• Data on other people in the area (also non-exposed); and
• Any potentially coincident factors in the community.

When an AEFI cluster has been identified, the cause-specific definitions provide a framework for
investigation and causality assessment. Usually, the key considerations will be to investigate the
possibility of an immunization error, vaccine reaction or a vaccine quality defect. For relatively
new vaccines or established vaccines used in new target population, a cluster may represent a
previously unrecognized vaccine product related reaction. Awareness of vaccine reaction rate and

32
background rate of reported event is essential for assessing a cluster in terms of the strengthen of
the signal it may provide (Fig. 3).

Figure 3: Identifying cause of AEFI cluster.

The possibility of immunization error must be considered when events cluster in one setting
without a similar change in frequency in other settings using the same vaccine. On the other hand,
if an increased frequency of events is reported from multiple settings the possibility of a quality
defect must be considered more strongly. Clusters of fainting after immunization are well-
recognized immunization anxiety-related reactions during immunization programs targeting
adolescent girls.

4.4.8. Laboratory testing of specimens

Laboratories have an important role in AEFI case diagnosis and case management. They also
have a key role in testing the quality of the samples of vaccines and the supplies used. Laboratory
tests for the purpose of AEFI case diagnosis and case management conducted on the patient (e.g.
blood, urine, radiology, ECG etc) are based on the provisional case diagnosis and
recommendations of the treating physician. These tests are considered “routine” and should be
performed in clinical laboratories. The results of these tests are important to confirm the case
diagnosis and arrive at the “valid diagnosis” for assessing causality.

Laboratory testing of samples of vaccines and supplies are rarely necessary. Laboratory testing
may sometimes confirm or rule out the suspected cause: the vaccine may be tested for sterility
and adjuvant (e.g. aluminium content); the diluent for sterility and chemical composition; and the

33
needles and syringe for sterility. Testing should be requested on a clear suspicion and not as
routine, and never before the working hypothesis has been formulated. Determining which
samples to send, if any, depends on the working hypothesis for the cause of the event(s) (Table
11). If the used vial of suspect vaccine is available, it should be sent with unused vials of the same
lot.

Table 11: Laboratory testing to investigate AEFIs by working hypothesis.

Working hypothesis: programme Specimen to send Laboratory test

error is suspected

Vaccine transportation or storage Vaccine vial Composition

Reconstitution error Vaccine vial and/or diluent Sterility or composition

(chemical)

Non-sterile injection Needle, syringe, vaccine vial Sterility

and diluent

Vaccine problem Vaccine vial Composition

4.5. AEFI causality assessment

Causality assessment of AEFI is a vital component of AEFI risk assessment, decision-making and
the initiation of action. Causality assessment is the systematic evaluation of the information
obtained about an AEFI to determine the likelihood that the event might have been caused by the
vaccine/s received. Causality assessment does not necessarily establish whether or not a definite
relationship exists, but generally ascertains a degree of association between the reported adverse
events and the vaccine/vaccination. Nevertheless, causality assessment is a critical part of AEFI
monitoring and enhances confidence in the national immunization programme. Vaccine recipients
want to know whether they experienced the event due to the vaccine. They may believe that
because one event followed another, it was causal. It may be difficult to explain that that this might
not have been the case. Causality assessment may provide a more descriptive explanation that may
reassure the vaccine and lead to better management of the event that ultimately helps the vaccinee.
In essence, determining whether or not an AEFI is attributed to the vaccine or vaccination decides
the steps needed to be taken to address the event. Causality assessment is important for:

• Identification of vaccine-related problems.

• Identification of immunization error-related problems.

34
• Excluding coincidental events.
• Detection of signals for potential follow-up, testing of hypothesis and research; and
• Validation of pre-licensure safety data with comparison of post-marketing surveillance safety
data.

The quality of the causality assessment depends on three factors:

• The performance of the AEFI reporting system in terms of responsiveness and effectiveness
(the quality of case reporting and follow-up investigation).
• Availability of adequate medical and laboratory services for the investigation and follow-up
of cases, and access to background information on population disease/illness rates in the
absence of vaccination; and
• The quality of the causality review process, including access to appropriate expertise.

4.5.1. Levels of AEFI causality assessment

Causality assessment of AEFI applies to investigating relationships between a vaccine and an

adverse event at three levels - the population level, the level of the individual AEFI case report,
and in the context of the investigation of signals – all of which depend on an assessment of
causality for individual cases.
Individual AEFI case report: The aim is to estimate the probability that the occurrence of a
reported AEFI in a specific individual is causally related to use of the vaccine. The aim of
causality assessment at the individual level is to address the question “Did the vaccine given to a
particular individual cause the particular event reported?” It is usually not possible to establish a
definite causal relationship between a particular AEFI and a particular vaccine on the basis of a
single AEFI case report.
Population level: Using surveillance data and an appropriate statistical methodology in order to
test the hypothesis that there is a causal association between the usage of a vaccine and a particular
AEFI. This may sometimes be combined with causality assessment at the individual level (of
AEFIs collected within that system) whereby some or all of the cases of interest could undergo
individual case review and causality assessment before inclusion in a group analysis.
Investigation of signals: The assessment of whether a particular vaccine is likely to cause a
particular AEFI takes into account all evidence from individual AEFI cases, surveillance data
and, where applicable, cluster investigations as well as nonclinical data. A review of the
corresponding adverse event reports should be performed to verify that the available
documentation is strong enough to suggest a new potential causal association, or a new aspect of
a known association, in order to justify further evaluation of the signal. The objective of signal

35
evaluation is to draw conclusions on the presence or absence of a suspected causal association
between an adverse event and a vaccine, and to identify the need for additional data collection or
for risk minimization measures. This may also prompt the regulatory authorities to request the
marketing authorization holder (MAH) for an additional analysis of its available data on a
particular event under investigation.

4.5.2. Criteria for causality in the causality assessment process

Criteria for causality are generally considered to have been derived from work by Bradford Hill in
1965 as the minimum conditions necessary to provide adequate evidence in support of a causal
relationship. While Hill indicated nine criteria, the following are most relevant to the question
“Can the given vaccine cause a particular event?”. The first criterion is essential.

• Temporal relationship: Exposure to the vaccine must precede the occurrence of the event.
Exposure always precedes the outcome. If factor “A” is believed to cause a disease, then it is
clear that factor “A” must always precede the occurrence of the disease. This is the only
absolutely essential criterion of causality.
• Biological plausibility: Biological plausibility may provide support for or against vaccine
causality. In other words, the association should be compatible with existing theory and
knowledge related to how the vaccine works.
• Strength of the association: The stronger the (statistical) association, the more likely that the
relation is causally associated.
• Consistency of the association: The association is consistent when results are replicated in
studies in different settings, among different populations and using different methods.
• Specificity: The vaccine is the only cause of the event that can be shown.
• Definitive proof that the vaccine caused the event: There is clinical or laboratory proof that
the vaccine caused the event. Consideration of alternative explanations: In doing causality
assessment, all reasonable alternative etiological explanations need to be considered.
• Prior evidence that the vaccine in question could cause a similar event: The concept of
“re-challenge” is more commonly used in medicine causality, but it has also been helpful for
certain vaccine-event considerations (e.g. Guillain-Barré syndrome or GBS occurring on three
separate occasions in the same individual within weeks of administration of tetanus vaccine).

4.5.3. Who should do causality assessment?

To ensure that the prerequisite criteria described above are met and to ensure broader acceptance
of the findings, causality assessment of AEFI should ideally be performed by a reviewing team or
committee of reviewers whose areas of expertise could include paediatrics, neurology, general

36
medicine, forensic medicine, pathology, microbiology, immunology and epidemiology. Other
external experts should be invited for the review of specific events. Causality assessment in
Ethiopia is done by the National Pharmacovigilance Advisory Committee (NPAC), that is:

• Independent
• Free of real or perceived government, and industry conflicts of interest
• Has broad range of expertise in the areas of ‘infectious diseases, paediatrics, epidemiology,
microbiology, pathology, immunology, neurology, cardiology, internal medicine,
pharmacology, clinical pharmacy and other relevant fields.
• The committee has written Terms of Reference (TOR) and decides independently but having
a support and close communication with EFDA.

4.5.4. Case selection for causality assessment

The selection of cases for causality assessment should focus on:

• Serious AEFI, as per the regulatory definition of serious
• The occurrence of events above an expected rate or of unusual severity
• Cluster of events
• Signals generated as a result of individual or clustered cases as these could signify a potential
for large public health impact.

• Other AEFI as decided by the review committee or an investigation team such as immunization
errors, significant events of unexplained cause occurring within 30 days after a vaccination
(not listed in the product label), or events causing significant parental or community concern.

4.5.5. Prerequisites/ basic requirements for causality assessment

Timely reporting of AEFI followed by appropriate and detailed investigation are important. The
information and evidence that is collected during a good quality AEFI investigation holds the key
for a successful evaluation of the event, the circumstances of its occurrence and provides vital
clues for the probable cause of its occurrence. An AEFI should fulfil four prerequisites before
causality assessment, namely:

• The AEFI case investigation should have been completed. Premature assessments with
inadequate information could mislead the classification of the event.
• All details of the case should be available at the time of assessment. Details should include
documents pertaining to the investigation as well as laboratory and autopsy findings as
appropriate.

37
• There must be a “valid diagnosis” (as explained below) for the unfavourable or unintended
sign, abnormal laboratory finding, symptom or disease in question.

• All vaccines and medicines that were administered before the event should be identified.

4.5.6. Steps for causality assessment of AEFI

There are four steps in causality assessment. The steps and their purpose are outlined below:
Step 1: Eligibility: To determine if the AEFI case satisfies the minimum criteria for causality
assessment as outlined below.
Step 2: Checklist: To systematically review the relevant and available information to address
possible causal aspects of the AEFI (Annex III)
Step 3: Algorithm: To obtain a direction/trend as to the causality with the information gathered
in the checklist.
Step 4: Classification: To categorize the AEFI’s association to the vaccine / vaccination based on
the direction determined in the algorithm.
WHO has developed an e-tool that will help assessors perform an AEFI causality assessment both
online and offline modes. Details are available at [Link] safety/causality-
assessment-software-EN/en/.
Step 1: Eligibility
To proceed with causality assessment, it is necessary to first confirm that the vaccine was
administered before the event occurred. This can be ascertained by eliciting a careful history with
the relevant stakeholders to ascertain the timing of vaccination with the onset of any signs and/or
symptoms related to the event being assessed. It is also essential to be clear on the “diagnosis” of
the reported AEFI. The valid diagnosis refers to a clinical sign, symptom, abnormal laboratory
finding, or disease with clear details as to onset. The diagnosis should also meet a standard case
definition for the disease process being assessed. If available, it is best to adopt one of the Brighton
Collaboration case definitions. However, if this is not possible, case definitions (Annex IV) can be
adapted from the standard medical literature, national guidelines or local clinical practice. If the
reported event does not have a valid diagnosis, it may not be possible to adequately categorize the
AEFI. Therefore, additional information should be collected to arrive at a valid diagnosis or clear
definition of what event is being assessed for causality against the given vaccination. Another
important point is that while the revised process envisages the causality assessment of an individual
AEFI case with a particular vaccine, in the event of multiple vaccines being given simultaneously,
a causality assessment may have to be conducted taking into account each vaccine separately.

38
 Case
defintions
valid
identify diagnosis Use appropriate case definitions (Brighton
collaboration, standard literature and
vaccine national definition or other approved
definition

AEFI Select unfavourable or unintended sign, abnormal

case laboratory finding, symptom or disease that is
suspected causally linked to the vaccine *

Identify one* of the vaccines administered before

this incident.

Ensure the AEFI investigation is completed and all details

of the case and keep all details in a retrievable manner
available documents are completed.

Figure 4: Case’s eligibility for causality assessment.

*For a given assessment only one valid diagnosis and one vaccine administered can be
assessed at one time. If multiple vaccines are administered to the patient at the same time, each
vaccine should be assessed separately; when faced with multiple presumptive diagnoses, the
reviewer should consider doing a separate causality assessment for each diagnosis. Likewise
for a cluster of AEFI, each individual case must be assessed separately.

If the investigated AEFI appears to not meet the eligibility criteria because of inadequate
information, attempts should be made to collect any additional information required in order to
ensure that the case can be properly assessed for eligibility. Additionally, all cases reported
(including those deemed or eventually deemed ineligible cases) should be stored in a repository
(preferably electronic) so that they can be accessed should additional information become
available through reports of similar cases, new evidence in the literature, or through periodic
database analysis. At the successful completion of this stage, the committee should define the
“causality question” as below.

Has the________________________vaccine /vaccination caused___________________ (Valid

Diagnosis)?

39
Step 2: Checklist

The checklist contains elements to guide the assessor or committee of reviewers to collate the
evidence for case review. It is designed to assemble information on patient-immunization-AEFI
relationships in the following key areas:

• Is there evidence for other causes?

• Is there a known association with the vaccine/vaccination in the medical literature? If so, did
the event under assessment occur within an appropriate time window and, if so, was it
associated with the vaccine product, an immunization error or immunization-related anxiety.
• Is there any strong evidence against a causal association?
• Other qualifying factors for classification (e.g. background rate of the event, present and past
health condition, potential risk factors, medication, biological plausibility, etc). Once the
checklist (Annex III) is systematically completed, the answers in the checklist are applied to
the algorithm.

Step 3: Algorithm

After the checklist is completed, data related to the association under investigation is ready to be
applied to the algorithm (Fig. 5). The algorithm aims to be a roadmap for the decision-making of
the reviewers, but it does not, and should not, take away the expert and deductive logical process
inherent in linking a diagnosis to its potential cause. The stepwise approach of the algorithm helps
to determine if the AEFI could be consistent or inconsistent with an association to immunization,
an indeterminate outcome or unclassifiable.

40
Figure 5: Causality assessment algorithm.

41
Step 4: Classification

The final classification is based on the availability of adequate information. The cause-specific
definitions provide clarity on “A. Consistent causal association to immunization” and “C.
Inconsistent causal association to immunization” (coincidental). The association is considered “B.
indeterminate” when adequate information on the AEFI is available but it is not possible to assign
it to either of the above categories. The details are presented in Fig. 6.

C. Inconsistent with causal

A. Consistent with causal association to immunization
association to immunization
B1. *Temporal relationship is C. Coincidental
A1. Vaccine consistent but there is Underlying or emerging
product-related reaction insufficient definitive condition(s), or
(Asper published evidence for vaccine condition(s) caused by
literature) causing event (may be new exposure to something
Adequate other than vaccine.
A2. Vaccine quality vaccine-linked event)
defect-related reaction
B2. Qualifying factors
Information A3. Immunization result in conflicting trends
error-related reaction of consistency and
inconsistency with causal
available A4. Immunization association to immunization.
anxiety-related reaction
(ISRR**)

Unclassifiable
Adequate Specify the additional
information required
for classification:
Information

not available

*B1: Potential signal and maybe considered for investigation

** Immunization stress related

Figure 6: Causality assessment classification.

4.5.7. Actions to be taken after causality assessment.

Determining causality is not an end in itself. The lessons learned should provide insights and way
forward for the technical, immunization program staff working at woreda, zonal and higher level.
Findings should be promptly and clearly communicated and the messages should be clear on any
next steps to be taken, including communicating reassurance or the need to take action around the
42
program including training, research, modifying systems, refining tools and revocation of
marketing authorization and recall of the vaccine and so on to avoid and/or minimize recurrences.
Based on global guidelines, EFDA and the EPI will take the following actions depending on
different causality conclusion resulting from the assessment.

A. Consistent causal association to immunization

A1. Vaccine product-related reaction

In vaccine-related reactions, decisions should be carefully thought out and the impact on the
immunization program, alternate sources of vaccine, and the reliability of the evidence on which
the decision is based needs to be carefully examined. Communication with the vaccine
manufacturer, UNICEF and WHO should be made before making any decision with regard to the
vaccine withdrawal.

A2. Vaccine quality defect-related reaction

If this reaction is related to a particular lot or batch, the distribution of the lot or batch has to be
ascertained and specific instructions must be provided on the utilization or non-utilization of the
lot or batch. It is important to inform the EFDA, the marketing authorization holder and global
partners such as WHO and UNICEF about the AEFI.

A3. Immunization error-related reaction

Training and capacity-building are critical to avoid recurrences of such reactions. Supervision and
follow up is also required.

A4. Immunization anxiety-related reaction

Depending on the solitary or cluster nature of the immunization anxiety-related reaction there are
separate approaches for prevention. Vaccination should take place in an ambient and safe
environment.

B. Indeterminate

B1. Consistent temporal relationship but insufficient evidence for causality

The details of such AEFI cases should be maintained in a national database, which can later help
to identify a signal suggesting a new potential causal association, or a new aspect of a known
association, between a vaccine and an event or set of related events.

B2. Conflicting trends of consistency and inconsistency with causality

These cases are classified on the basis of available evidence. If additional information becomes
available, the classification can move into a more definitive category. During the assessment, the
43
reviewers should clarify what additional information would be helpful to finalize the causality
assessment and should seek information and expertise from national or international resources.
The Global Advisory Committee on Vaccine Safety (GACVS) can be approached for guidance
through WHO, particularly when an event is likely to impact the immunization programme
significantly.

C. Inconsistent causal association to immunization (coincidental)

The information and confirmation should be provided to patients, their relatives, the healthcare
provider and the community.

D. Ineligible cases and Unclassifiable cases

Cases ineligible for causality assessment are those where the amount of information available to
the assessor is limited such that a causality question cannot be created. For example, the reviewer
does not have information on the type of vaccines administered to the patient or the clinical details
are insufficient to formulate a causality question. Cases may also be considered ineligible prior to
the assessment if the investigation is incomplete, and the essential information is not available.

Unclassifiable cases occur in instances where the reviewer is able to formulate a causality question,
but during the process of assessment discovers that some important elements are missing to enable
a logical classification. For both ineligible and unclassifiable cases, it is important to specify the
missing elements and make attempts to obtain the information so that causality assessment could
be attempted again. It is essential that the available details of such cases are placed in a central
repository that the investigators can revert back to when additional information that would help
with the causality assessment is available. If AEFI causality is not established, depending on the
nature of the event, its extent and whether it is on-going, a further investigation or epidemiological
study may be warranted. However, it must be accepted that in some cases the relationship to
vaccine will never be clear.

4.6. Action and response to AEFI

Considering the situation or event, responding to AEFI may be immediate short-term activities
or/and long-term follow-up activities. Follow-up activities should be based on findings of
investigations, causality assessments and recommendations by the investigation/expert
committees. Major follow-up actions may have an impact on the national immunization
programme, as well as on regional and global programmes and planning.

44
4.6.1. Patient care

It is of utmost importance to ensure that proper and early treatment is received by affected
vaccinees (patients), regardless of the diagnosis. Mild symptoms such as mild fever and pain are
likely to be of short duration and can be managed by assuring and educating parents during
immunization. Health professionals need to know how to recognize AEFI, how to treat them or
refer them to a clinician/hospital and must report AEFI as soon as possible. Concomitantly with
the patient management these cases should be documented in the AEFI case reporting form and
reported to the responsible body.

4.6.2. Follow-up actions

Depending on the nature of the event(s), the number of people affected, and community
perceptions, an investigation may be conducted. In general, it is not advisable to discontinue the
immunization program while awaiting the completion of the investigation. If AEFI causality is not
established – depending on the nature of the event, its extent and whether it is ongoing – a further
investigation or epidemiological study may be warranted (Table 12). However, it must be accepted
that in some cases the relationship to vaccine will never be clear. Communication and training are
two important follow-up actions that have long term implications.

Table 12: Actions to be taken upon completion of the investigation/causality assessment.

Type of AEFI Follow-up action

Vaccine-related If there is a higher reaction rate than expected from a specific vaccine or
reaction lot, EFDA should obtain information from the manufacturer and consult
with the WHO and UNICEF to consider:
• withdrawing that lot.
• investigating with the manufacturer.
• Obtaining vaccine from a different manufacturer.
Immunization Correct the cause of the error. This may mean one or more of the
error related following:
• changing logistics for supplying the vaccine.
• changing procedures at the health facility.
• training of health professionals.
• Intensifying supervision.
Whatever action is taken, it is important to review at a later date to check
that the immunization error related events have been corrected.

45
 Coincidental The main objective is to present the evidence showing that there is no
indication that the AEFI is a vaccine-related reaction or immunization-
related error and, that the most likely explanation is a temporal
association between the event and vaccine/vaccination. This
communication can be challenging when there is widespread belief that
the event was caused by immunization.

Sometimes, it may be useful to enlist further expert investigation to

ensure that the event was truly coincidental. The potential for
coincidental events to harm the immunization program through false
attribution is immense.
Communication and training are two important follow-up actions that have long-term implications.
They should not necessarily be focused on an individual event, but they should emphasize the need
for programme managers and others involved in immunization to pay attention.

4.6.3. Logistics

Immunization supply chain, injection safety and waste management are part of immunization
safety surveillance. It is highly recommended to improve supply chain system and ensure safe
injection practices. The EPI, Ethiopian Pharmaceuticals Supply service (EPSS) and EFDA needs
to plan and work harmoniously to improve the immunization safety surveillance system.
Improving logistics will be the appropriate response in regard to program errors that can be traced
to the lack of supplies or equipment or to a failure in the cold chain or inadequate skills.

5. AEFI Data Management

The AEFI data management system involves all courses from data generation to having the
analysed or synthesized information for action and/or appropriate communication. AEFI data and
its proper management is important at all levels. AEFI surveillance should include structured,
systematic and permanent data collection on the safety of vaccines used in the country’s
immunization program. Managing the collected data is one of the basic components of the AEFI
surveillance system. The data management cycle starts from the source of AEFI data and ends
with provision of feedback, as depicted below:

46
Figure 7: Data management cycle.

5.1. Sources of AEFI data

Information on vaccine safety and the possible occurrence of AEFIs can be obtained from clinical
examinations, interviews of health professionals, care givers and community leaders, review of
charts and registers (ANC, OPD and Immunization), vaccine and vaccine supplies ledger,
observation of immunization administration, sub-national PV centres, vaccine handling and
storage and diagnostic reports (laboratory reports, imaging reports, etc…). Management of data
on AEFIs consists of reviewing data from the following sources:

• Individual case safety report (individual AEFI report)

• Data collected into a line list (Annex V)
• Case investigation forms
• Laboratory information (Human and vaccine related)
• Records about similar events in the community
• Records of the implicated vaccine and vaccine related supplies
• Review of published information from journal/article
• Data from Medicine Regulatory agencies

47
5.2. Data entry

Data entry is expected to occur at health facility, woreda/zonal, regional and national PV centres
for AEFIs detected during immunization. Data entry can be affected using common electronic
tools; e-reporting/web-based reporting and Med Safety mobile app. Data received through hard
copy, email and line list will be entered at regional and national PV centres using Vigiflow. In this
regard, to avoid duplication of data at all levels, an effort has to be made while compiling and
submitting the report including notification of the primary reporter to the next higher level. AEFI
data should be entered as soon as possible at all levels. However, during campaigns, overall data
entry may be performed on completion of surveillance, investigation and post-campaign survey
activities. All reporting forms and other data-collection tools completed during the investigations
and surveys shall be submitted to the central level with copies kept at various levels.

5.3. Data Analysis and Interpretation

Before analysing an entered AEFI data, it will be cleaned and validated at all levels in order to
ensure data quality. All reported AEFI cases should be line-listed at all levels using the AEFI
line-list which enable us to get the aggregate data which is the first step of data management.
Basic time, place and person analysis should be done by the woreda/zone and regional program
managers. Other key analysis areas that relate to the performance of the surveillance system at all
levels include.

• Reporting source (reports of AEFI by different sources may provide a wider range of
information)
• Completeness of submitted AEFI forms.
• Verification and reassurance of data accuracy
• Identifying health institutions where AEFI are not reported (determining whether this is due
to failure of reporting or whether there are no AEFI to be reported) and checking on “zero
reporting” or “nil reporting”.
• Performance of investigated cases (except in health facilities)
• Performance of causality assessment to classify the AEFI (mandatory for national)
• Estimated AEFI reporting rates (assessing the number of reported AEFI and the rate per 1000,
10, 000 or 100, 000 doses of vaccine used in a specified time period).
• Estimated rates by type of AEFI and by antigen (assessing the number of cause specific
reported AEFI and the rate for 1000, 10 000 or 100 000 doses of vaccine used in a specified
time period).

48
• Comparison of the observable rates with available or expected known events, whether vaccine
reactions or background rates or historic reporting trends (mandatory for national level)

5.3.1. Responsible body for data analysis at different levels

Prior to the analysis of the line list at the national level, it is important to re-check the case
definitions adopted by the reporting sources. The case should fit into a case definition such as the
Brighton collaboration case definitions or any definition selected by the National
Pharmacovigilance Advisory Committee. Data analysis could be carried out by the responsible
focal persons at different levels in the vaccine safety surveillance system. Analysis of data at
woreda/zonal level is important to identify programme errors. This helps to take corrective action
in a timely manner. Table 13 below describes the type of analysis and the purpose.

Table 13: Types and purpose of data analysis at different levels.

Program What data to analyse Purpose of data analysis at given level

implementation
level
Number of reports clinics, These are program operation/surveillance
hospitals, villages by a given performance indicators (timeliness,
time completeness)
Local level
Reported AEFIs by place. Identification of immunization related errors
(Immunization
(clinics, hospitals), persons will lead to corrective action
provision level)
and time
Reported AEFI by antigen Will identify vaccine reactions and
coincidence
Number of reports by local These are program operation /surveillance
levels performance indicators (timeliness,
completeness) at local level.
Reported AEFI by place. Identification of immunization related errors
Sub national
(clinics, hospitals), will lead to corrective action
level (Regional/
persons and time
zone/ woreda)
Cluster analysis Cluster analysis leads to identify
immunization related errors, coincidence and
vaccine reactions

49
 Reported AEFI by antigen Will identify vaccine reactions and
coincidence
Number of reports by These are program operation /surveillance
intermediate levels performance indicators (timeliness,
completeness) at intermediate level
Reported AEFI by place Will identify vaccine reactions, including
(clinics, hospitals), persons signals detection.
National level and time
Cluster analysis Cluster analysis leads to identify
immunization related errors, coincidence and
vaccine reactions
Reported AEFI by antigen Leads to taking operational and policy
decisions in the country

Investigation data analysis consists of reviewing the case investigation report for each client,
reviewing other data about the event (such as immunization practices at session sites and vaccine
lot numbers and expiration dates) and the community in which it took place, making a final
diagnosis, and identifying the probable cause. It might not be possible to make a diagnosis, the
cause might not be evident, or there might be more than one cause. However, the investigation
team should try to collect as much information as they can from the data.

The number of vaccine product-related reactions will naturally increase with increased vaccine
use, so it is essential to calculate antigen (vaccine) specific adverse reaction reporting rate. In
considering concerns with specific lots, it is important to have accurate denominator of vaccine
use as possible, as it is always the rate and not the number of reports that needs evaluation
(comparison with known vaccine product-related rates).

5.3.2. Steps in AEFI data analysis and interpretation

Step 1: All reported AEFI cases should be line listed.

Line listing will help for initial identification of clusters or any unusual or significant reported
events that need further analysis.

Step 2: Tabulating AEFI data by place, person, time, antigens, and type of events

This step further filters the AEFI by different variables and helps program managers to generate
clues for further analysis. Even at this step, it is possible to identify common immunization errors.

50
For example, increased number of abscesses at an immunization centre is more likely due to
immunization error. However, further investigation of such observation is necessary to verify the
causality.

Step 3: Calculating AEFI rates.

Number of doses administered for each antigen is the denominator for calculating reported AEFI
rates for each antigen in a given time period (by month, quarter or year). Analysis shall expand
to the AEFI rates by first or second or third dose, when the antigen is administered more than
once. For this, the number of doses administered of the given antigen by first, second or third
doses need to be used as the denominator.

For example, in region X, registered under-1 year child population is 5000. The coverage of
measles vaccine is 90%. During the same year, 20 febrile seizures were reported following
measles vaccination. How to calculate rate of febrile seizures? The numerator for this vaccine
reaction (febrile seizures) is 20. The most challenging selection is to use a proper denominator.
There are a few options for selecting a denominator (Table 14).

Table 14: Options for selecting a denominator.

Denominator Limitations

Administered doses of vaccines Most reliable, but not often available

Distributed doses Greater than administered doses, thus may reduce rate
(underestimate)

Coverage x population May be less accurate because of variability in coverage estimates

Target population Proxy measure for vaccine population (may also underestimate)

Given = Population (<1 yr) = 5000; coverage = 90% and AEFI cases (Febrile Seizure) = 20

In this example, since no other data are available, it can use coverage to get the denominator.

Denominator = Population x coverage = 5000 * 90% = 4500

The reported febrile seizures rate is 20/4500*100 = 0.44%

The use of proper multiplier is important as it may vary by purpose and level of analysis. At local
level, percentage (%) is the best choice, whereas sub-national and national levels may use 1000,
100,000 or million as multiplier. For common, minor vaccine reactions, percentage is
recommended and for rare and serious reactions, 10,000 (104), 100,000 (105) or 1 000, 000 (106)
can be used.
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Step 4: Comparison and interpretation of rates

Available expected vaccine reaction rates for each type of AEFI for an antigen (Tables 4 and 5)
present a guide to make a decision on corrective action to be taken on reported AEFI. It is also
important to know about background rates of reported medical events in the country.

• Background rates are independent and not related with the vaccine.
• Observed (reported) rates include both background rates and vaccine-related rates.

Comparison of background rates with reported rates (observed) of AEFI will lead to a valid
conclusion on causality of these events as being due to a vaccine reaction. Based on the above
data analysis results, proper interpretation is important for decision making (Table 15).

Table 15: Terminology and interpretation on type of rates.

Terminology Definition How is this Example

measured

Background Rate of an event Background If we measured the

rate (occurring/ reported/ rates can be temperatures
measured) due to all determined in a of a population of 1,000
cases fitting the case population prior unvaccinated children for
definition, which are to the one week, some children
expected to occur in the introduction of a would present a fever
community in the new vaccine or (defined as >38°C) during
absence of the putative simultaneously the time of observation (e.g.,
vaccine. in non‐ infections). For example, a
vaccinated rate of 2 cases of fever per
people. 1000 children per week.

Observed This is the The observed rate If we observe the same

(reported) background rate can be measured in population of 1000children
rate PLUS the additional pre‐licensure but we now vaccinate all
clinical trials or children and measure their
effect of the vaccine.
post‐licensure temperatures daily there will
studies be a greater rate of fever.
Thus, the rate of fever may

52
 increase to 5/1000children
per week, with the increase
concentrated in the 72 hours
that follow vaccination.

Vaccine This is the rate of Randomized Thus, the vaccine attributable

reaction rate an event that is clinical trials which rate of fever will be
(attributable caused by the are placebo 3/1000vaccinated children
rate). vaccine–that is a controlled. (that is the observed rate
minus the background rate)
vaccine reaction. Post‐licensure
studies ‐passive
surveillance.

The following graphic shows a comparison of the background rate with the observed rate of an
event to determine the vaccine reaction rate (i.e. the rate of events that are actually caused by the
vaccine)

Figure 8: Vaccine reaction rate, observed rate and background rate.

Factors to be considered when comparing rates of AEFIs are summarized in Table 16.

Table 16: Factors to consider when comparing rates of AEFIs.

53
 Vaccines
Although a vaccine may have the same antigens, different manufacturers may produce vaccines
(or lots of the same vaccine) that differ substantially in their composition, including the presence
of an adjuvant or other components. These variations result in vaccines with different
reactogenicity (the ability to cause vaccine reactions), which in turn affects the comparison of their
vaccine-attributable rates.
Age
The same vaccine given to different age groups may result in different vaccine-attributable rates.
For example, MMR vaccine given to infants may cause febrile convulsions. This symptom does
not occur in adolescents who are given the same vaccine.
Vaccine dose
The same vaccine given as a ‘primary dose’ may have a different reactogenicity profile than when
it is given as a ‘booster dose’.
Case definition
Adverse event may be defined differently in surveillance / research studies that do not stick to the
same case definition. Not using standardized case definitions may consequently affect the
estimation of the AEFI rate. Brighton Collaboration has developed cases definitions for many
vaccines reactions.
Surveillance methods
The way that surveillance data are collected may alter the rate. For example, surveillance data may
be collected actively or passively, using pre- or post-licensure clinical trials, with or without
randomization and placebo controls.
Background conditions
The background rate of certain events may differ between communities. This can influence the
observed rate even though the vaccine-attributable rate is the same in both communities. For
example, reports of death post-vaccination may be higher in a country that has a higher background
rate of deaths due to coincidental infection.
At all levels, data analysis and interpretation shall be done on monthly basis however during
campaign and special concerns, the analysis and interpretation shall be done immediately.

5.3.3. Consideration of causality

Until the investigation is complete a working hypothesis is all that can be formulated. Later it will
be possible to analyse the data, assign a cause and classify it into one of the categories of AEFI.
For a few medical events, the diagnosis itself will show the cause whether it is immunization error-

54
related or vaccine-related or coincidental or injection reaction (e.g. injection site abscess). In other
cases, additional information may be required as external evidence to identify the cause.

Comparing background data with reported (observed) data does not conclude the causality. It only
generates the hypothesis. To conclude that a vaccine causes a particular vaccine reaction, it is
necessary to demonstrate that the risk in vaccinated individuals is greater than that in the non-
vaccinated, provided that the effects of confounders and bias are ruled out. Estimating relative risk
and attributable risk is necessary, and retrospective or prospective analysis of available data or
designing epidemiological studies (case series, case-control, cohort or ecological studies) will
confirm causality.

Decision and feedback: This is also one part of data management. Decision could be made based
on the evidence generated or data transformation while feedback will be provided based on the
nature of the case.

Data handling, storage and sharing: AEFI data or information needs not only generation but
also management of the data including proper handling or storage. Besides, data security, properly
sharing it to the relevant stakeholders and partners in accordance with the requirements stated in
the safety data sharing SOP of EFDA requires consideration. Regular and timely sharing of data
to the regional and global community is important to maximize resources and capacity for
decision making, improves signal detection and identification of very rare events. Data
transformation is usually required to facilitate data sharing. As national dashboard of vaccine
safety data is important to improve data visibility and facilitate data sharing, EFDA in
collaboration with stakeholders should strive to develop and implement. For additional
information on monitoring and evaluation aspects of the AEFI surveillance refer to the M & E
section of this guideline.

6. Stakeholders in AEFI Monitoring

The EFDA is responsible to ensure that all medicines, including vaccines are safe, effective and
of good quality. On the other hand, the EPI program of the MOH is responsible for preventing
disease, disability and death by providing safe and effective vaccine to children and adults to
prevent and control vaccine-preventable diseases.

AEFI monitoring in Ethiopia needs to be a collaborative effort between the EFDA and various
stakeholders, including; the EPI at the MOH, EPHI, regional health bureaus and regulatory bodies,
regional and national task forces of AEFI, professional associations, academic institutions, Market
Authorization Holders (MAHs) (manufacturers, importers and distributors), health institutions,
EFDA and branch offices, Regional PV Centres, EPSS, Health professionals, AEFI Taskforces,

55
National Pharmacovigilance Advisory Committee, clients including guardians and all concerned
local and international development partners.

6.1. Roles and Responsibilities of key stakeholders

6.1.1. MOH/National Immunization Program

• Engage EFDA in the planning, implementation, monitoring& evaluation of EPI.

• Collaborate with EFDA in mobilizing resources to strengthen AEFI monitoring.

• Coordinate the national immunization taskforce/technical working group (TWG) and

consider AEFI as priority agenda.

• Collaborate with EFDA in the continuous development, revision and distribution of tools
and guidelines for AEFI surveillance.

• Provide capacity building to strengthen the system on AEFI monitoring and case
management in collaboration with EFDA.

• Facilitate and ensure AEFI case management at healthcare facilities.

• Provide support to regions, zones and woredas on AEFI monitoring.

• Share AEFI reports received from routine immunization and campaigns with EFDA.

• Ensure that balanced vaccine safety information is communicated through media to prevent
the public from biased information.

• Ensure the implementation of AEFI related recommendations/ decisions reaching up to the

lower level.

6.1.2. EFDA

• Monitor and evaluate implementation of AEFI surveillance in collaboration with

stakeholders.

• Design and adopt new AEFI monitoring initiatives.

• Revise, update, distribute and ensure availability of AEFI monitoring tools.

• Strengthen Pharmacovigilance Advisory Committee and provide secretariat service for

causality assessment.

• Strengthen AEFI data management system at all levels.

• Share AEFI data to relevant stakeholders and global community.

56
 • Provide and follow training of personnel involved in AEFI surveillance in collaboration
with other stakeholders.

• Analyse AEFI data and providing feedback to stakeholders.

• Establish stakeholders’ coordination platform.

• Carry out risk- benefit analysis of vaccine used in the immunization program.

• Take the necessary corrective measures when there is a safety and/or quality problem of
vaccine is observed.

• Communicate AEFI and immunization safety that needs public attention at the national
level with MOH.

• Establish /strengthen efficient communication mechanisms on vaccine safety among

stakeholders.

• Support regions and strengthening AEFI documentation and reporting system.

• Engage in the planning, training, implementation and monitoring of related activities

organized by MOH-EPI

• Collaborate with MOH-EPI mobilizing resources to strengthen AEFI monitoring.

• Engage in national immunization taskforce/TWG.

• Verify submission and review of risk management plans prior to market authorization and
making recommendation for post authorization safety surveillance.

• Oversee the monitoring of vaccine safety by reviewing periodic safety update report
(PSUR) and periodic benefit-risk evaluation report (PBRER)

The branch EFDA offices coordinate AEFI monitoring activities in collaboration with sub
national stakeholders in their respective areas.

6.1.3. Ethiopian Public Health Institute (EPHI)

• Collaborate with EFDA during AEFI surveillance.

• Conduct laboratory analysis of specimens collected during AEFI investigation.
• Collaborate with EFDA during outbreak response vaccination campaign.
• Conduct epidemiological studies related to vaccine safety monitoring in collaboration
with EFDA.
• Collaborate on post marketing clinical trials of vaccines.

57
6.1.4. Regional EPI and Regulatory bodies

In the AEFI monitoring system regional EPI and regulatory bodies are responsible for: -

• Monitoring of timely reporting of AEFI cases by health professionals

• Collaboration with EFDA branch offices on AEFI monitoring activities.

• Collaboration with EFDA on sharing of AEFI related information, training materials,

relevant tools

• Provide AEFI monitoring trainings to health professionals.

• Handling and timely dissemination of well-organized information to community

• Coordinating and strengthening AEFI investigation taskforce

• Collaboration and facilitate AEFI case investigation to ensure timely completion of

investigation.

• Conduct AEFI case investigations and share reports to EFDA for causality assessment.

• Strengthen AEFI data documentation and sharing.

• Ensure that AEFI kits are available at vaccination sites.

• Plan and evaluate performance of AEFI monitoring activities.

• Ensure that regulatory recommendations and decisions related to AEFI monitoring are
implemented in their respective areas.

6.1.5. Woreda and Zonal EPI and regulatory bodies

In the AEFI monitoring system, Woreda and Zonal EPI and regulatory bodies are responsible for:

• Monitor and ensure AEFI detection, collection and reporting by health professionals.

• Collaborate with EFDA branch offices, regional EPI and regulatory bodies on AEFI
monitoring activities.

• Collaborate with regional investigation taskforce during AEFI case investigation.

• Document AEFI data and share with the next higher level.

• Ensure the availability of AEFI kits at vaccination sites.

• Monitor and evaluate the performance of AEFI activities.

• Follow and ensure the implementation of regulatory recommendations and decisions.

58
 • Ensure incorporation of AEFI activities in woreda based planning, micro plan and
administrative planning.

6.1.6. EFDA Branch Offices

In the AEFI monitoring system EFDA branches are responsible for: -

• Monitoring of timely reporting of AEFI cases by health professionals

• Collaborate with EFDA on sharing of AEFI related information, training materials,

relevant tools.

• Provide trainings to health professionals on AEFI monitoring.

• Handling and timely dissemination of well-organized information to community

• Coordinate and strengthen AEFI investigation taskforce.

• Collaborate and facilitate AEFI case investigation to ensure timely completion of

investigation.

• Conduct AEFI case investigations and share reports to EFDA for causality assessment.

• Strengthen AEFI data documentation and sharing.

• Ensure availability of AEFI kit at vaccination sites

• Conduct planning and performance evaluation of AEFI monitoring actives.

6.1.7. Regional Pharmacovigilance Centres (RPVCs)

In the AEFI monitoring system RPVCs are responsible for: -

• Timely report AEFI cases in their hospitals

• Collaborate with EFDA branch offices on AEFI monitoring activities.

• Collaborate with EFDA on sharing of AEFI monitoring activities.

• Ensure organized AEFI data documentation.

• Ensure availability of AEFI kit at vaccination sites of hospital

• Closely work in hospitals service delivery points

6.1.8. National Pharmacovigilance Advisory Committee (NPAC)

The national pharmacovigilance advisory committee is composed of a multidisciplinary expert and

with an independent decision-making power. It conducts causality assessment based on the
available data and provide a recommendation to EFDA.

59
The NPAC is responsible for:

• Assess potential causal links between AEFIs and AESIs and vaccines.

• Monitor AEFI data for identification of potential signals of previously unidentified vaccine
related adverse events.

• Review all serious AEFIs presented for expert opinion and arrange further investigation to
establish causality, if required.

• Communicate with other national and international experts, when required, to establish
causality and resolve vaccine quality issues.

• Advise NRAs, EPIs on vaccines AEFI- and AESI-related issues when requested.

• Advise the Ministry of Health (MoH) on vaccines and Immunization safety-related matters
when requested.

6.1.9. The parent/guardian

Parents and guardians should follow health professionals’ advice for:

• Applying simple home remedies (e.g. correct positioning of the child when sleeping,
increasing intake of fluids, sponging, breast feeding, antipyretics etc.) for managing minor
AEFIs

• Returning immediately to health care facilities if severe/serious AEFI occurs

• Notify health professionals of any AEFI encountered.

6.1.10. The health professionals

• Advise vaccine recipients or their parents/care givers about AEFI management and
notification.

• Detection, management and recording of AEFIs.

• Notification and reporting of AEFIs using the standard reporting tools.

• Keep AEFI monitoring related documents properly such as AEFI line list, copy of reported
serious AEFIs.

• Properly document patient medical chart after management of suspected AEFI

• Collaborate with AEFI case investigation taskforce during investigations.

• Implement feedback provided on AEFI monitoring from higher administrative level.

60
6.1.11. Developmental Partners

• Sharing of global good practices on AEFI monitoring

• Plan for AEFI monitoring activities in collaboration with the national PV centre.

• Provide technical and financial support for AEFI monitoring activities.

• Ensure appropriate mobilization of resources.

61
7. Safety Communication

Vaccine safety communication is crucial for the successful implementation of an immunization program
and to maintain public trust and confidence in the vaccination programs. It is essential in at least three
situations:

• Explaining properly the benefits and expected AEFIs of a recommended vaccine.

• Addressing public concerns and upcoming or persistent rumours about vaccine safety
• Preparing to address vaccine safety crises if and when they occur.

Communication with parents/guardians, the community, HCPs and the media need to be carried out
under many circumstances, from launching new vaccines and putting in place mass immunization
campaigns to issuing reminders to maintain vaccinations up to date. When a vaccine safety
investigation is under way as a result of a report of an AEFI, communications involve keeping the public
informed about the investigation, the results, and actions already taken or to be taken regarding the
AEFI. At the same time, it is crucial to highlight the benefits of immunization even while
communicating about an investigation.

The overall goal of vaccine safety communication is to maintain public trust in vaccines and
immunization safety to sustain the immunization program and achieve a high level of immunization
coverage. The specific objectives of vaccine safety communication are to:

• Enable parents/guardians and communities understand the importance of vaccines and

immunization.
• Restore confidence in vaccines and express trust in the national immunization programme.
• Support parents/guardians complete their children’s immunization schedules.
• Enable program managers, health professionals, the media and other stakeholders to deal with
vaccine safety related rumours and misinformation.
• Enable the mass media and social media to disseminate accurate and evidence-based information
about vaccine safety.
• Timely communicate AEFI causality assessment classification results

Identification of particular interest groups and their representatives should be part of an overall
communication strategy. Decisions including what, when, whom and how to communicate should be
part of an overall communication strategy. It is very important to understand the nature of an AEFI and
62
also whether it is real or perceived, because any AEFI can become a crisis situation if not handled
correctly and wisely.

7.1. Vaccine safety communication during crisis

A crisis related to a vaccine is an unexpected series of events that may happen after a vaccine has been
administered to a population group particularly during or at the end of a campaign. A crisis may arise
when something goes wrong, for example as a result of genuine vaccine reactions or due to
immunization-related errors that cause parents/guardians to withhold immunization of their children. A
crisis may be caused by media publicity about an AEFI incident, even if it may have no basis or is
triggered by unfounded rumours. The crisis may be made worse by a “cover-up” that is subsequently
found out. This is why programme managers must act in a timely manner by mobilizing the
communication task force, the technical group, spokespersons and media partners to dispel any
misinformation quickly before it becomes a crisis.

Crisis communication is a combined effort by health and immunization programme managers, the
regulatory authority and local leaders to address public concern about vaccine safety through
appropriate channels. Messages should assure the public that a vaccine safety issue is being investigated
and will be resolved, and that the immunization programme will continue.

7.2. Communication with stakeholders

There are many parties to whom communications should be tailored in order to meet their particular
needs. These include:

• Parents/guardians and the community

• Health professionals
• Particular stakeholders such as the MOH, EPHI, EPSS, politicians, professional associations,
academia, international agencies and development partners, such as WHO, UNICEF,
Pharmacovigilance Advisory Committee, regional investigation task force, policy makers and other
government authorities, health facilities, MAHs and
• The media

The following principles of communication apply to most of the stakeholders:

• Listen empathetically to concerns.

• Reassure and support but do not make false promises.
• Communicate frequently.
• Build up and maintain relationship among the stakeholders.
63
• Inform audiences about possible common adverse events and how to handle them.
• Prepare fact sheets on adverse events and other key information for all audiences.
• Continuously communicate during the investigation period in order to ensure understanding both of
the situation and of the balance of risk and benefit of vaccination

Do not apportion blame, especially on the HCPs, but focus on the correction and quality of the national
immunization programme.

7.2.1. Communication with clients, parents/guardians and the community

Key points to consider when communicating with the vaccine recipient (patient or client) or
parents/guardians, and the community are:

• Listen to the clients’, parents/guardians’ and the community’s concerns empathetically.

• Reassure and support the client and/or parent/guardian but do not make false promises.
• Prepare and provide a fact sheet on adverse event for the clients and/or parents/guardians and the
community.
• Inform the individual client and/or parent/guardian about possible common adverse events and how
to handle them.
• Continuously communicate with the client and/or parent/guardian and the community during the
investigation

7.2.2. Role of health professionals in community communication on AEFI

Vaccinators at various levels need to be able to provide information to parents/guardians and handle
queries from the community, especially from parents/guardians. Those who routinely administer
vaccines, or who evaluate and treat patients, including medical officers, clinical officers and nurses,
should receive training and regular updates on vaccine safety and quality issues, news and research.
Health professionals and vaccinators should be trained about vaccine safety communication to share
accurate immunization facts, respond to questions, clarify possible doubts, and motivate families to
adopt healthy behavioural practices, including using immunization services.

Once an AEFI has occurred, HCPs should do the following:

• Communicate immediately with the immediate higher level in the EPI, regulatory and EFDA.
• Provide the parents with factual information.
• Reassure parents/guardians and the community that necessary measures are being taken.
• If the AEFI is caused by an immunization error, inform the parents/guardians and the community
what steps are being taken to prevent similar events in the future.
64
 • Reassure the public about the safety of vaccines.

7.2.3. Communication with health professionals

Because of the nature of their work, HCPs should have some training, or at least experience in
communication skills. Communication with HCPs by EFDA and investigators should be sensitive to
their needs. Therefore:

• Communication should include all levels of health authorities involved.

• Reassure the staff of their knowledge, ability, skills and performance.
• Do not blame HCPs but focus on the correction and quality of the national immunization
programme.
• Keep HCPs updated on the investigation process, progress, and findings

7.2.4. Communicating with community and/or religious leaders

Community and/or religious leaders are regarded by their constituents as credible sources of
information. They have the power to shape public opinions and can improve the links between families,
communities and health services. Religious leaders can serve as effective communication channels and
social mobilizers when it comes to combatting rumours and unfounded negative opinions about vaccine
safety. The community and/or religious leaders should be informed about any upcoming major EPI
event such as new vaccine introduction, mass campaign etc., so that they take the lead during
communication and social mobilization. When there is a crisis, early communication with community
and/or religious leaders is very important. An advocacy kit with briefing notes and scripted key
messages, that they could use to communicate with their constituents, should be provided to them.

7.3. Communicating with the Media

The media is an important gateway to inform the public and shapes their view and attitudes towards
vaccines and immunization, especially including the occasional vaccination campaigns. In the long-
term, building partnerships with the media is key to keep the public regularly informed about
immunization, its benefits and to motivate families and communities to make use of immunization
services.

Effective communication with the media includes advance preparation. This is part of a communication
plan and is particularly important before a new vaccine is introduced or before and during an
immunization campaign. A communication plan can also provide ongoing communication support to
routine immunization programmes. Table 17 lists the elements of a good media plan for communication.

65
Table 17: Media plan for communication.

Database of journalists • Maintain a list of print and electronic media journalists covering
health with contact information
• Update regularly any changes in the media list

Information packages • An information package may contain the following documents in

both hard copy and e-copies:
• Frequently asked questions (FAQs) on immunization in general and
for AEFI
• Fact sheet or a technical brief on a specific vaccine’s safety
background rates of AEFI and expected AEFI rates
• Recent updates such as statistics, progress made in the country,
globally
• Contact addresses of spokespersons (experts) in the MOH,
regulatory authorities and other stakeholders
• The information package needs to be updated regularly.

Media releases • Must specifically answer the 7 Ws for journalists:

• Who is affected/is responsible?
• What has happened?
• What is being done?
• Where has it happened?
• When did it happen?
• Why did it happen?
• Will it happen again?

Information specific to • Local media are read and believed by more people in the community

media characteristics than national media

• National media have a wide reach and influence national agendas
• International media can influence national agendas

Spokesperson system The MOH and/or EFDA:

• Identify an appropriate spokesperson(s)

66
 • May delegate this responsibility to RHBs if deemed necessary.
• Share contact details of spokesperson.
• Ensure spokesperson(s) has experience or training in dealing with the
media

Note: The MOH and/or EFDA shall be responsible for communicating the AEFI to media, public and
stakeholders to limit the possibility of conflicting messages coming from different sources and
unauthorized channels.

Media interest is usually greatest initially when relatively little is known. In this environment, rumours
can flourish and the potential for harm is huge. A media conference, convened early even if there is
only very limited information to give, can provide a uniform message to all at the same time, thus
avoiding conflicting messages. This will also prevent the circulation of rumours and build a relationship
with reporters. Professional organizations and other stakeholders may have greater credibility than the
government, particularly in a crisis situation. Providing them an opportunity for their unified support
for immunization and the approach being taken to handle/investigate the problem can help considerably.

7.4. Follow-up actions with communications

Keeping promises: If it has been promised that updates about the investigation will be disseminated,
make sure that this is done by the promised date. If the findings have been delayed, ensure that the delay
is communicated.

Providing answers to unanswered questions: If a question cannot be answered for any reason, get
back to the requestors with the answers as soon as possible.

Keeping the public informed about subsequent developments: If any decision or action is taken at
the highest levels following the AEFI investigations, or during the investigations, and the public must
know about it, keep them informed through a press release to the media or other locally appropriate
means. The MOH website [Link] and the EFDA website [Link] can be used as an
excellent interface to provide updated information.

67
8. Monitoring and Evaluation of AEFI Surveillance system

Monitoring and Evaluation (M&E) is very essential in the health system in general and in monitoring
AEFI surveillance system. The overall AEFI surveillance system should be monitored and evaluated at
all levels of surveillance cycle (Fig. 1). This system could be examined with usual M&E parameters:
the input or resources used to conduct the activities or the processes for attaining the immediate result
or output and medium-term results or outcome to the community, and ultimately the long-term impact
to the entire population.

The overall goal of monitoring AEFI is early detection and timely response to AEFI, to minimize
negative effects to the health of individuals and of population. In this connection, the effort or
performance of AEFI surveillance system needs to be regularly measured at all levels using appropriate
indicators to ensure that the system is sensitive enough to identify and respond to AEFI effectively.

8.1. Monitoring arrangements/ platforms

The following platforms will be used for monitoring of the AEFI activities.

Periodic Reports: weekly, monthly, quarterly and annually using selected AEFI indicators as
appropriate.

Review Meeting: this could be arranged by Performance Monitoring Team (PMT) of respective
structure of health facility, Woreda, Zone, RHB/RRB and national level, monthly, quarterly, biannual
and annually depending on the context.

Supportive Supervision: is a process that individuals or groups of people from relevant stakeholders’
conduct site visit to a specific facility to promote quality at all levels of the health system by
strengthening relationships within the system, focusing on the identification and resolution of problems,
and helping to optimize the allocation of resources, promotion of high standards, teamwork, and
facilitation of two-way communications.

Supportive supervision at all levels should be conducted based on a predefined checklist developed to
assess the progress of key aspects of AEFI monitoring. EFDA or its branch, RHB, WoHOs, ZHDs, and
health facility management should have clearly defined objectives and a timeline to provide regular
supportive supervision. The onsite supportive supervision for AEFI monitoring can be carried out
independently or integrated with other EPI activities. The frequency of supportive supervision at sub
national level will be at least on quarterly basis under regular condition within appropriate time while
at the national level it will be carried out at least biannually.

68
Depending on the context, additional monitoring platforms such as during campaigns and other special
conditions could be considered. Continuous monitoring and periodic evaluation of AEFI using quality
data enable us to measure and improve performance and to make decisions in a timely manner. The
parameters could be extracted from the logical process as inputs indicators; availability of plan,
resources, tools and materials, while for the process indicators include the activities conducted to
achieve the desired output.

A similar approach could be used to have indicators for measuring the outcome and impact parameters.
The indicators are expected to give a panoramic view of the AEFI landscape and criteria to select
appropriate indicators are practicality/ accessible and feasible, pertinent/relevant, simple (in terms of
time, money and complexity), sensitive, specific, verifiable, technically valid/ importance of the
information. These context-based criteria and standard references could be used to select the
measurement indicators. Furthermore, a few of these will be considered in the DHIS2 tracking system.

8.2. AEFI monitoring Indicators.

a) Input Indicators
• Availability of AEFI tools (recording and reporting forms)
• Availability of AEFI job aids (guideline, SOPs)
• Availability of plan for AEFI monitoring
• Availability of budget for AEFI monitoring
• Availability of assigned focal person in health facilities for AEFI monitoring.
• Availability of functional regional investigation taskforce
• Availability of functional National Pharmacovigilance Advisory Committee
b) Process and outputs indicators.
• Number of professionals trained on AEFI monitoring/ PV in the past 2 years.
• Number of AEFIs detected from the number of vaccinations provided.
• AEFI reporting rate per 100 000 population.
• AEFI reporting rate per 100 000 < 5 years population.
• AEFI reporting rate per 1 000 000 administered doses of vaccines.
• AEFI reporting ratio in surviving infants from a sub-national area or country per year.

This is calculated as: AEFI reporting ratio per 100,000 surviving infants per year.

Number of AEFI cases reported from a subnational area/country per year

= 𝑥 100,000
Total number of surviving infants in the same subnational area/country per year

69
• % of AEFI reports with completed critical information (completeness of reports)
• Percentage of SAEs reported on time (< 24 hours of notification) to the national level.
• Percentage of serious AEFI cases for which investigation is initiated on time (within 15 days of
receipt of report).
• Percentage of ICSR entered into the vigiflow.
• Percentage of ICSR on vigiflow shared to the global database.
• Functionality of regional investigational task force
• Proportion of causality assessment conducted from investigated AEs
• Proportion of causality assessment completed within 30 days of receipt of investigation report.
• Proportion of feedback/ responses provided for SAEs (excluding acknowledgement letter)
• Number of regulatory decisions (recommendation, action) taken in the reporting period.

Table 18: Brief description on M&E Key Performance Indicators for AEFI

SN Type of Level of Data Frequency Baseline

Indicator Indicator Data Source of data Target
Collection collection/
Analysis
1. Availability of AEFI Input All levels Document Quarterly
monitoring plan Review
2. Functionality of Output RHB Records Annually
Regional TF
3. AEFI reporting ratio in Output All levels Reg book Monthly
surviving infants
4. Proportion of causality Records Annually
assessment conducted Output
from investigated
SAEs
5. Proportion of Output National Records Annually
feedback/ responses
provided for SAEs
(excluding

70
 acknowledgement
letter)

9. References

1. Covid-19 vaccines: safety surveillance manual. Geneva: World Health Organization, 2020.
2. Global manual on surveillance of adverse events following immunization. Geneva: World Health
Organization, 2016.
3. Guideline for Surveillance and Response to Adverse Events Following Immunization. Addis Ababa:
EFMHACA, 2018.
4. Guidelines for AEFI Surveillance. Rwanda Food and Drugs Authority, 2022.
5. Guidelines for Surveillance of Adverse Events Following Immunization. Tanzania Medicines &
Medical Devices Authority, 2022.
6. [Link]
[Link].
7. [Link]
8. Immunization safety surveillance: Guidelines for managers of immunization programmes on
reporting and investigating Adverse Events Following Immunization. World Health Organization,
2015.
9. Marzouk, M, Omar M, Sirison K and et al. Evaluation of National Vaccination Implementation: A
Scoping Review of How Frameworks and Indicators Are Used in the Public Health Literature.
Vaccines 2022, 10, 567. [Link]
10. Module 15: Monitoring and data management. Geneva: World Health Organization, 2017.
11. Monitoring and Evaluation of AEFI during OCV mass vaccination campaigns. World Health
Organization, 2014.
12. National Assessment of AEFI monitoring system. Addis Ababa: Ethiopian Food and Drug
Authority, 2022 (unpublished).
13. National Implementation Guideline for Expanded Program on Immunization. Addis Ababa:
Ministry of Health, 2021.
14. National Clinical Pharmacy Service Implementation Manual in Ethiopia. Addis Ababa: Ministry of
Health, 2020.

71
10. Annexes

Annex I: AEFI Reporting Form

72
73
Annex II: AEFI Investigation Form

74
75
76
77
78
Annex III: The causality assessment checklist.

Y NU K NA Remarks

I. Is their strong evidence for other causes?

1. In this patient, does the medical history,

clinical examination and/or investigations,
confirm another cause for the event?

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

Vaccine product

1. Is there evidence in published peer reviewed

literature that this vaccine may cause such an
event if administered correctly?

2. Is there a biological plausibility that this

vaccinecould cause such an event?

3. In this patient, did a specific test demonstrate

thecausal role of the vaccine?

Vaccine quality

4. Could the vaccine given to this patient have a

quality defect or is substandard or falsified?

Immunization error

5. In this patient, was there an error in

prescribing or non-adherence to
recommendations for use of thevaccine (e.g.
use beyond the expiry date, wrong recipient
etc.)?

6. In this patient, was the vaccine (or diluent)

administered in an unsterile manner?

79
 7. In this patient, was the vaccine’s physical
condition (e.g. color, turbidity, presence of
foreign substances etc.) abnormal when
administered?

8. When this patient was vaccinated, was there an

error in vaccine constitution/preparation by
the vaccinator (e.g. wrong product, wrong
diluent, improper mixing, improper syringe
filling etc.)?

9. In this patient, was there an error in vaccine

handling (e.g. a break in the cold chain during
transport, storage and/or immunization
session etc.)?

10. In this patient, was the vaccine

administered incorrectly (e.g. wrong
dose, site or route of administration;
wrong needle size etc.)?

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

Y NU N Remarks
K A

Immunization anxiety (Immunization stress related responses - ISRR)

11. In this patient, could this event be a stress

response triggered by immunization (e.g. acute
stress response, vasovagal reaction,
hyperventilation, dissociative neurological
symptom reaction etc.)?

II (time): Was the event in section II within the time window of increased risk (i.e.‘Yes” response
to questions from II 1 to II 11 above)

80
12. In this patient, did the event occur within a
plausible time window after vaccine
administration?

III. Is there strong evidence against a causal association?

1. Is there a body of published evidence (systematic

reviews, GACVS reviews, Cochrane reviews
etc.) against a causal association between the
vaccine and the event?

IV. Other qualifying factors for classification

1. In this patient, did such an event occur in the past

after administration of a similar vaccine?

2. In this patient, did such an event occur in the past

independent of vaccination?

3. Could the current event have occurred in this patient

without vaccination (background rate)?

4. Did this patient have an illness, pre-existing

conditionor risk factor that could have contributed
to the event?

5. Was this patient taking any medication prior to the

vaccination?

6. Was this patient exposed to a potential factor (other

than vaccine) prior to the event (e.g. allergen, drug,
herbal product etc.)?

81
Annex IV: Examples of AEFI case definitions*

AEFI Case definition Vaccine

Anaphylaxis A clinical syndrome characterized by sudden onset (within one

hour), rapid progression of signs and symptoms involving
multiple (more than two) organ systems:

Skin: urticaria (hives), angioedema (swelling of face/body),

generalized erythema, bilateral red and itchy eyes of new onset

Respiratory: expiratory wheeze and inspiratory stridor

documented by a healthcare professional, cough and/or sneezing
and/or runny nose that is new onset and persistent, All
respiratory distress (tachypnoea, cyanosis, grunting, chest wall
retractions, increased use of accessory respiratory muscles and
measured hypoxia with oxygen saturation <90%.)

Cardiovascular: low blood pressure (hypotension) or reduced

circulation (fast weak pulses), loss of consciousness

Gastrointestinal: new onset vomiting and diarrhea (for infants

<12 months old, there must be two or more episodes)

BCG osteitis/ Inflammation of the bone with isolation of Mycobacterium bovis BCG
osteomyelitis BCG strain.

Disseminated Widespread infection occurring within 1 to 12 months after BCG BCG

BCG infections vaccination and confirmed by isolation of Mycobacterium bovis
BCG strain. Usually in immuno-compromised individuals.

Encephalopathy Abnormal level of alertness /consciousness or seizures, difficulty Measles,

with initiating and maintaining respiration, depression of tone Pertussis

82
AEFI Case definition Vaccine

Fever Endogenous elevation of at least one measured body temperature All

of ≥38 °C

Hypotonic, Event of sudden onset occurring within 48 (usually less than 12) Mainly
Hyporesponsive hours of vaccination and lasting from one minute to several hours, DPT,
Episode (HHE or in children younger than 10 years of age. All of the following must rarely
shock-collapse) be present: others

• limpness (hypotonic)

• reduced responsiveness (hypo responsive) or

unresponsiveness

• pallor or cyanosis – or failure to observe/ recall.

Injection site Fluctuant or draining fluid-filled lesion at the site of injection. All
abscess Bacterial if evidence of infection (e.g. purulent, inflammatory injectable
signs, fever, positive bacterial culture), Sterile abscess if no vaccines
evidence of bacterial infection on culture. Erythema, pain to light
touch, warmth at the injection site sterile abscesses is usually due
to the inherent properties of the vaccine.

Intussusception [Link]. Major criteria Rotavirus

• Surgical criteria:

The demonstration of invagination of the intestine at

surgery.

o and/or

• Radiologic criteria:

The demonstration of invagination of the intestine by

either air or liquid contrast enema; or

The demonstration of an intra-abdominal mass by

abdominal ultrasound with specific characteristic

83
AEFI Case definition Vaccine

features2that is proven to be reduced by hydrostatic enema

on post reduction ultrasound;

o and/or

• Autopsy criteria:

The demonstration of invagination of the intestine.

[Link]. Minor criteria

o Predisposing factors: age <1 year and male sex.

o Abdominal pain

o Vomiting

o Lethargy

o Pallor

o Hypovolemic shock.

o Plain abdominal radiograph showing an abnormal

but non-specific bowel gas pattern.

IS occurring within 42 days following immunization.

Lymphadenitis Either at least one lymph node enlarged to >1.5 cm in size (one BCG
(includes adult finger width) or a draining sinus over a lymph node.
suppurative Almost exclusively caused by BCG and then occurring within 2 to
lymphadenitis) 6 months after receipt of BCG vaccine, on the same side as
inoculation (mostly axillary).

Persistent Inconsolable and continuous crying lasting 3 hours or longer DPT,

inconsolable accompanied by high-pitched screaming. Pertussis
screaming

Seizures Occurrence of generalized convulsions that are not accompanied All,

by focal neurological signs or symptoms. Febrile seizures: if especially
temperature elevated >100.4 0F or 38 0C (rectal) Pertussis,
Measles

84
AEFI Case definition Vaccine

Afebrile seizures: if temperature is normal

Sepsis Acute onset of severe generalized illness due to bacterial infection All
and confirmed (if possible) by positive blood culture. injectable
vaccines

Severe local Redness and/or swelling cantered at the site of injection and one All
reaction or more of the following: injectable
vaccines
• Swelling beyond the nearest joint

• Pain, redness and swelling of more than 3 days and

interfering with daily activities.

• Requires hospitalization.

Local reactions of lesser intensity occur commonly and are trivial

and do not need to be reported.

Toxic shock Abrupt onset of fever, vomiting and watery diarrhoea within a few All
syndrome (TSS) hours of immunization. Often leading to death within 24 to 48 injectable
hours. vaccines

Vaccine Acute onset of flaccid paralysis and neurological deficits, OPV

Associated compatible with diagnosis of poliomyelitis, with isolation of
Paralytic vaccine virus and absence of wild virus in stool.
Poliomyelitis
(presenting as
AFP)

AEFI Case definition Vaccine

Anaphylaxis A clinical syndrome characterized by sudden onset (within one

hour), rapid progression of signs and symptoms involving
multiple (more than two) organ systems: All
Skin: urticaria (hives), angioedema (swelling of face/body),
generalized erythema, bilateral red and itchy eyes of new onset

85
AEFI Case definition Vaccine

Respiratory: expiratory wheeze and inspiratory stridor

documented by a healthcare professional, cough and/or sneezing
and/or runny nose that is new onset and persistent,

respiratory distress (tachypnoea, cyanosis, grunting, chest wall

retractions, increased use of accessory respiratory muscles and
measured hypoxia with oxygen saturation <90%.)

Cardiovascular: low blood pressure (hypotension) or reduced

circulation (fast weak pulses), loss of consciousness

Gastrointestinal: new onset vomiting and diarrhea (for infants

<12 months old, there must be two or more episodes)

BCG osteitis/ Inflammation of the bone with isolation of Mycobacterium bovis BCG
osteomyelitis BCG strain.

Disseminated Widespread infection occurring within 1 to 12 months after BCG BCG

BCG infections vaccination and confirmed by isolation of Mycobacterium bovis
BCG strain. Usually in immuno-compromised individuals.

Encephalopathy Abnormal level of alertness /consciousness or seizures, difficulty Measles,

with initiating and maintaining respiration, depression of tone Pertussis

Fever Endogenous elevation of at least one measured body temperature All

of ≥38 °C

Hypotonic, Event of sudden onset occurring within 48 (usually less than 12) Mainly
Hyporesponsive hours of vaccination and lasting from one minute to several hours, DPT,
Episode (HHE or in children younger than 10 years of age. All of the following must rarely
shock-collapse) be present: others

• limpness (hypotonic)

• reduced responsiveness (hypo responsive) or

unresponsiveness

• pallor or cyanosis – or failure to observe/ recall.

86
AEFI Case definition Vaccine

Injection site Fluctuant or draining fluid-filled lesion at the site of injection. All
abscess Bacterial if evidence of infection (e.g. purulent, inflammatory injectable
signs, fever, positive bacterial culture), Sterile abscess if no vaccines
evidence of bacterial infection on culture. Erythema, pain to light
touch, warmth at the injection site sterile abscesses is usually due
to the inherent properties of the vaccine.

Intussusception [Link]. Major criteria Rotavirus

• Surgical criteria:

The demonstration of invagination of the intestine at

surgery.

o and/or

• Radiologic criteria:

The demonstration of invagination of the intestine by

either air or liquid contrast enema; or

The demonstration of an intra-abdominal mass by

abdominal ultrasound with specific characteristic
features2that is proven to be reduced by hydrostatic enema
on post reduction ultrasound;

o and/or

• Autopsy criteria:

The demonstration of invagination of the intestine.

[Link]. Minor criteria

o Predisposing factors: age <1 year and male sex.

o Abdominal pain

o Vomiting

o Lethargy

o Pallor

87
AEFI Case definition Vaccine

o Hypovolemic shock.

o Plain abdominal radiograph showing an abnormal

but non-specific bowel gas pattern.

IS occurring within 42 days following immunization.

Lymphadenitis Either at least one lymph node enlarged to >1.5 cm in size (one BCG
(includes adult finger width) or a draining sinus over a lymph node.
suppurative Almost exclusively caused by BCG and then occurring within 2 to
lymphadenitis) 6 months after receipt of BCG vaccine, on the same side as
inoculation (mostly axillary).

Persistent Inconsolable and continuous crying lasting 3 hours or longer DPT,

inconsolable accompanied by high-pitched screaming. Pertussis
screaming

Seizures Occurrence of generalized convulsions that are not accompanied All,

by focal neurological signs or symptoms. Febrile seizures: if especially
temperature elevated >100.4 0F or 38 0C (rectal) Pertussis,
Measles
Afebrile seizures: if temperature is normal

Sepsis Acute onset of severe generalized illness due to bacterial infection All
and confirmed (if possible) by positive blood culture. injectable
vaccines

Severe local Redness and/or swelling centered at the site of injection and one All
reaction or more of the following: injectable
vaccines
• Swelling beyond the nearest joint

• Pain, redness and swelling of more than 3 days and

interfering with daily activities.

• Requires hospitalization.

Local reactions of lesser intensity occur commonly and are trivial

and do not need to be reported.

88
 AEFI Case definition Vaccine

Toxic shock Abrupt onset of fever, vomiting and watery diarrhoea within a few All
syndrome (TSS) hours of immunization. Often leading to death within 24 to 48 injectable
hours. vaccines

Vaccine Acute onset of flaccid paralysis and neurological deficits, OPV

Associated compatible with diagnosis of poliomyelitis, with isolation of
Paralytic vaccine virus and absence of wild virus in stool.
Poliomyelitis
(presenting as
AFP)

*Note: Brighton Collaboration has developed detailed case definitions for many vaccines reactions that
are available at [Link].

Annex V: AEFI Line List Format

AEFI line listing form for compilation at woredas or zonal/regional and national level to identify trends
and clusters of AEFI.

Year: _______: ______________

89
 Name/ID of an AEFI

related
case (write vertical)
Kebele (write name

(Write code)
vertical)
Woreda (write name
vertical)
Zone (write name

[A1] Vaccine- [A2]

vertical)
Region

Final Causality Classification

error-related
Immunization
Date of birth
(dd/mm/yyyy) and

Reported by: ____________________

Designation: _____________________
Date of immunisation

[A3]
Age (write vertical
(dd/mm/yyyy) (write
Reaction (code)
typeand
date of birth age
vertical)
[1] Minor [2]

Immunization
anxiety-related
below
Outcome (1)

90
Severe/Serious (write
(Recovered disability
Suspected vaccine

[B]
code only)
(2) /Died (3) (write
(name and dose, e.g.
Vaccine
code only) batch/Lot
Penta-2)
number
Diluent batch number

[C]
Onset time interval
(hours, days, weeks)
Date reporting
(dd/mm/yyyy)
Investigated? (If yes,

[D]
date dd/mm/yyyy)

classify
Final diagnosis

Date: ___________________________
Signature: _______________________
Indeterminate Coincidental Inadequate Result of causality
information to assessment