Global Manual Revised 12102015

WHO Library Cataloguing-in-Publication Data
Global manual on surveillance of adverse events following immunization.
1.Immunization Programs. 2.Adverse Drug Reaction Reporting Systems. 3.Vaccination – adverse effects. I.World
Health Organization.
ISBN 978 92 4 150776 9 (NLM classification: WA 115)
© World Health Organization 2014 (Revised March 2016)
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Acknowledgements
This manual has been developed by WHO under the guidance of the Global Advisory
Committee on Vaccine Safety (GACVS). The GACVS members included Ananda Amarasinghe
(lead author), Michael Gold, Robert Pless, Xavier Kurz, Gagandeep Kang, Ambrose Isah and
Brigitte Keller-Stanislawski. Significant inputs were provided by the CIOMS Working Group
on Vaccine Safety, the Brighton Collaboration and WHO regional and country offices. The
WHO secretariat in Geneva supporting the work included Madhava Ram Balakrishnan and
Patrick Zuber.
This manual has been developed on the basis of the Guidelines for immunization programme managers
on surveillance of adverse events following immunization (second edition) published by the WHO
Western Pacific Regional Office in 2012.
Contents
Glossary .................................................................................................................v
Abbreviations............................................................................................................ viii
1. Purpose............................................................................................................... 1
2. Principles of immunization and understanding vaccines............................... 3
2.1 Immunity........................................................................................................ 3
2.1.1 Active immunity.................................................................................... 4
2.1.2 Passive immunity................................................................................... 4
2.1.3 Herd immunity...................................................................................... 4
2.1.4 How does immunization work?............................................................. 4
2.2 Vaccines......................................................................................................... 5
2.2.1 Classification of vaccines....................................................................... 6
2.2.2 Other components of vaccines (excipients)............................................. 9
2.3 Contraindications and precautions................................................................ 10

3. Adverse events following immunization....................................................... 13
3.1 Vaccine reactions.......................................................................................... 14
3.1.1 Cause-specific vaccine reactions.......................................................... 14
3.1.2 Vaccine reactions by seriousness and frequency................................... 15
3.1.3 Prevention and treatment of vaccine reactions..................................... 16
3.2 Immunization error-related reactions............................................................. 17
3.3 Immunization anxiety-related reactions......................................................... 20
3.4 Coincidental events...................................................................................... 21
4. Immunization safety surveillance system...................................................... 25
4.1 Objectives..................................................................................................... 25
4.2 Types of immunization safety surveillance..................................................... 26
4.3 Steps for establishing an immunization safety surveillance system................. 27
4.4 Roles and responsibilities of the NRA in immunization safety surveillance...... 29
4.5 Roles and responsibilities of the immunization programme in immunization
safety surveillance......................................................................................... 30
4.5.1 Roles and responsibilities at the level of the immunization service
provider.............................................................................................. 30
4.5.2 Roles and responsibilities at the subnational level of immunization
services............................................................................................... 31
4.5 3 Roles and responsibilities at the national level of immunization
services............................................................................................... 33
4.5.4 Roles and responsibilities of immunization providers in the
private sector...................................................................................... 34
4.6 Terms of reference of the National Immunization Safety Expert Committee... 35
4.7 Monitoring and evaluating the immunization safety surveillance system....... 37
4.8 Differences between surveillance of AEFI and adverse events linked to
other medical products................................................................................. 38
5. Reporting AEFI................................................................................................. 43
5.1 Which events should be reported?................................................................ 43
5.2 When to report?........................................................................................... 45
5.3 How to report?............................................................................................. 45
5.4 Reporting AEFI during immunization campaigns........................................... 47
5.5 Barriers to reporting...................................................................................... 47
5.6 Private-sector reporting................................................................................. 48
5.7 Vaccine Adverse Events Information Management System (VAEIMS)............. 48
6. Investigating AEFI............................................................................................ 51
6.1 Why AEFI reports should be investigated....................................................... 51
6.2 Which AEFI reports should be investigated?.................................................. 51
6.3 Who should investigate AEFI?....................................................................... 52
6.4 When to investigate AEFI.............................................................................. 52
6.5 How to investigate AEFI................................................................................ 53
6.6 Laboratory testing: vaccine........................................................................... 54
6.7 Laboratory testing: human specimens........................................................... 55
6.8 Investigating AEFI clusters............................................................................. 57
6.9 Investigation of deaths.................................................................................. 58
7. Analysis of AEFI data....................................................................................... 63

7.1 Who should analyse the data?...................................................................... 64
7.2 How should the data be analysed and interpreted?....................................... 65
7.3 How should a cause be determined?............................................................ 68
8. Causality assessment of an AEFI..................................................................... 71
8.1 Levels of AEFI causality assessment............................................................... 72
8.2 Scientific basis : criteria for causality in the causality assessment process....... 73
8.3 Case selection for AEFI causality assessment................................................. 74
8.4 Steps to be taken before starting a causality assessment............................... 74
8.5 Causality assessment method....................................................................... 75
8.6 Action to be taken after causality assessment............................................... 81
9. Actions and follow-up to AEFI........................................................................ 85
9.1 Patient care.................................................................................................. 85
9.1.1 Management of suspected anaphylaxis or collapse after vaccination.... 85
9.2 Follow-up actions......................................................................................... 87
9.2.1 Logistics.............................................................................................. 88
9.3 Training and training opportunities for vaccine safety.................................... 89
9.3.1 E-learning course on vaccine safety basics........................................... 89
9.3.2 Vaccine safety basic training................................................................ 90
9.3.3 Vaccine safety advance training........................................................... 90
10. Communication................................................................................................ 93
10.1 Communication with stakeholders.............................................................. 94
10.2 Communicating with the media.................................................................. 95
10.3 Preparing key messages.............................................................................. 97
10.4 Crisis management..................................................................................... 98
Annex 1. Frequency of Vaccine Adverse Reactions of commonly used vaccines...... 100

Annex 2. AEFI Reporting Form............................................................................... 103
Annex 3. AEFI Investigation Form........................................................................... 104
Annex 4. AEFI Line listing....................................................................................... 108
Annex 5. Causality Assessment: Step 2 (Event Checklist)........................................ 109
Tables and Figures
Table 1 Classification of vaccines
Table 2 Cause-specific categorization of AEFI (2012)
Table 3 Frequency of occurrence of reported adverse reactions
Table 4 Immunization error-related adverse reactions
Table 5 Estimated number of coincidental infant deaths that could be temporally linked to
immunization (e.g. with DTP/PVV) in the month, week and day after immunization
in selected countries
Table 6 Critical control functions of country NRA by vaccine sources
Table 7 Checklist for immunization safety surveillance system
Table 8 List of example of reportable AEFI
Table 9 Core variables with minimum information required for reporting in AEFI
surveillance
Table 10 Laboratory testing to investigate AEFI by working hypothesis
Table 11 Guide to human specimen samples collection following selected AEFI
Table 12 Cause-specific cluster characteristics
Table 13 Actions to safeguard the public during an investigation
Table 14 Purpose of data analysis at different levels
Table 15 Options for selecting a denominator
Table 16 Factors to consider when comparing rates of AEFI
Table 17 Usefulness and limitations of standardized case causality assessment
Table 18 Assessing causality at different levels
Table 19 The causality assessment checklist
Table 20 Conditions that maybe mistaken for anaphylaxis post-immunization
Table 21 Actions to be taken upon completion of the investigation/causality assessment
Table 22 Media plan for communication
Figure 1 Programme implementation level, responsibility and surveillance activities

Figure 2 Steps in an AEFI investigation
Figure 3 Identifying the causes of an AEFI cluster
Figure 4 Vaccine reaction rate, observed rate and background rate
Figure 5 Causality assessment: eligibility
Figure 6 Causality question
Figure 7 Causality assessment: algorithm
Figure 8 Causality assessment: classification
Global manual on surveillance of adverse events following immunization
Glossary
Adverse event Any untoward medical occurrence which follows

following immunization immunization and which does not necessarily have a causal
(AEFI)* 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, causality assessment is

a systematic review of data about AEFI case(s) in order 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 that is 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.
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).
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September 2014
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 from infectious diseases, since
most microbes are identified as foreign by the immune
system.
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.
Immunization safety A system for ensuring immunization safety through

surveillance detecting, reporting, investigating and responding to AEFI.
Non-serious AEFI An event that is not “serious” and does not pose a potential
risk to the health of the recipient.
Non-serious AEFI should also be carefully monitored because
they may signal a potentially larger problem with the vaccine
or immunization, or may have an impact on the acceptability
of immunization in general.
Safe injection practice Practices which ensure that the process of injection carries
the minimum of risk, regardless of the reason for the injection
or the product injected.
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.
Signal* (safety signal) Information (from one or multiple sources) which suggests a
new and potentially causal association, or a new aspect of a
known association, between an intervention and an adverse
event or set of related adverse events, that is judged to be of
sufficient likelihood to justify verificatory action.
Surveillance The continuing, systematic collection of data that are

analysed and disseminated to enable decision-making and
action to protect the health of populations.
Trigger event A medical incident following immunization that stimulates a

response (usually a case investigation).
vi
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,

pharmacovigilance* assessment, 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 product-related An AEFI that is caused or precipitated by a vaccine due

reaction* to one or more of the inherent properties of the vaccine
product, whether the active component or one of the other
components of the vaccine (e.g. adjuvant, preservative or
stabilizer).
Vaccine quality defect- An AEFI that is caused or precipitated by a vaccine that is

related reaction* due to one or more quality defects of the vaccine product,
including its administration device as provided by the
manufacturer.
Vaccination failure* Vaccination failure may be defined on the basis of clinical

endpoints or immunological criteria where correlates or
surrogate markers for disease protection exist. Primary failure
(e.g. lack of seroconversion or seroprotection) needs to be
distinguished from secondary failure (waning immunity).
Vaccination failure can be due to (i) failure to vaccinate (i.e.
an indicated vaccine was not administered appropriately for
any reason) or (ii) because the vaccine did not produce its
intended effect.
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 that 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.
*Source: Definition and application of terms for vaccine pharmacovigilance. Report of the CIOMS/WHO Working Group on Vaccine
Pharmacovigilance. Geneva: Council for International Organizations of Medical Sciences; 2012 (http://www.who.int/vaccine_safety/
initiative/tools/CIOMS_report_WG_vaccine.pdf accessed 25 July 2014).
vii
September 2014
Abbreviations
AEFI Adverse event following immunization
BCG Bacillus Calmette-Guerin vaccine for tuberculosis (TB)
CIOMS Council for International Organizations of Medical Sciences
DT Diphtheria-tetanus vaccine
DTP Diphtheria-tetanus-pertussis vaccine
DTaP Diphtheria-tetanus-pertussis (acellular) vaccine
DTwP Diphtheria-tetanus-pertussis (whole-cell) vaccine
EPI Expanded Programme on Immunization
HHE Hypotonic hyporesponsive episode
Hib Haemophilus influenzae type b vaccine
ICH International Conference on Harmonization
IPV Inactivated poliovirus vaccine
LAV Live attenuated vaccine
MMR Measles-mumps-rubella vaccine
NRA National regulatory authority
NCL National control laboratory
OPV Oral poliovirus vaccine
PCV Pneumococcal conjugate vaccine
PvV Pentavalent (DTP-HepB-Hib) vaccine
TSS Toxic shock syndrome
VAPP Vaccine-associated paralytic poliomyelitis
VPD Vaccine-preventable disease
WHO World Health Organization
viii
1
Purpose
Immunization is one of the most effective public
health interventions for protecting the individual
and the public from vaccine-preventable diseases
(VPDs). Immunization has saved millions of lives.
Modern vaccines are safe and effective. However, like
other medicinal products, vaccines are not free from
adverse reactions.
Vaccines rarely cause serious adverse reactions, and

common reactions are minor and self-limited. We
monitor the safety of vaccines by looking for adverse
events following immunizations (AEFI). An AEFI may
be caused by a vaccine reaction but often, particularly
if the event is serious, the event is coincidental to
vaccination. Other events may be caused by an
error in administration or handling of the vaccine.
Irrespective of the specific cause, an AEFI may lead
to public suspicions of vaccines and parents may refuse further immunization for their
children, making them susceptible to VPDs which are disabling and life-threatening.
Vaccine pharmacovigilance, which includes the surveillance of AEFI (i.e. systematic
collection of data on medically important events following immunization, which provides
information on investigation leading to necessary follow-up action), should be part of
all immunization programmes as this helps sustain public confidence in the programme.
This manual provides guidance for the managers of immunization programmes (and
others responsible for vaccine safety and quality) on the following:
n strategies and systems for ensuring quality and safety of vaccines;

n the objectives of vaccine and immunization safety surveillance;
n AEFI surveillance system: reporting, investigation, causality assessment and the new
classification of cause-specific AEFI;
n understanding vaccine reactions for better decision-making;
n the best use of surveillance data;
n response processes, including a communication strategy on immunization safety for
the public and the media.
As VPDs become less prevalent as a result of effective immunization programmes,
more public attention will be given to AEFI. New vaccines are being added to the
programmes and the schedule contains more vaccine antigens, with some included in
multivalent vaccines. For example, instead of the trivalent vaccines (DTP), most countries
1
September 2014
are now using either tetravalent (DTP-Hib or DTP- HepB) or pentavalent (DTP-HepB-
Hib) combined vaccines. With emerging diseases such as H1N1 influenza, demand for
seasonal and pandemic influenza vaccines has grown. An increase in the number of
vaccines given (e.g. in mass immunization campaigns) will lead to more AEFI, with some
being associated with vaccines or immunization and others being unrelated to them (i.e.
due to coincidental events). Immunization error-related reactions (previously known as
“programme error”) may also increase. Reporting and investigating AEFI can be used to
identify and correct immunization error-related reactions and may help to distinguish an
inconsistent coincidental event from a vaccine reaction and other immunization-related
events. AEFI surveillance allows for proper management of AEFI and avoids inappropriate
responses to reports of AEFI that can create a sense of crisis. For example, without an
immunization safety surveillance system a coincidental event may be mistaken for a
vaccine reaction and could lead to inappropriate suspension of a vaccine programme.
Public awareness of vaccine safety has grown through increased access to information
through the internet, television and other media. In addition, the vigilance of health-
care providers with regard to vaccine safety has increased due to the strengthening of
AEFI surveillance. As a result, more concerns about the quality and safety of vaccines
are highlighted and more information is demanded by the public and service providers.
In this increasingly complex situation, to determine whether a vaccine is causally linked
to an AEFI or the AEFI is a mere coincidence requires detailed investigation and causality
assessment. In order to maintain and improve public confidence in national immunization
programmes, all health-care providers should be aware of AEFI and be prepared to
respond to public concerns. Timely response to public concerns about the safety of
vaccines, as well as prompt communication, will protect the public and preserve the
integrity of the immunization programme.
The goals of these guidelines are to improve the efficiency and quality of AEFI surveillance
activities – and thus strengthen the quality of immunization programmes at national
and regional levels – and to ensure the immunization safety of all recipients of vaccines.
Who will use this manual?

KEY POINTS
This manual will be useful for immunization programme managers, staff

of the national regulatory authority (NRA) at national and subnational
levels, immunization service providers at institutions and in the field, staff
of pharmacovigilance centres and other stakeholders in immunization
services.
2
2 Principles
immunization and
understanding vaccines
of
2.1 Immunity
Immunity is 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 from infectious diseases, since most
microbes are identified as foreign by the immune
system. Immunity to a microbe is usually indicated by
the presence of antibody to that organism (antigen,
immunogen). Immunity is generally very specific to
a single organism or to a group of closely-related
organisms.
There are two basic mechanisms for acquiring immunity: active and passive.
2.1.1 Active immunity

Active immunity is the stimulation of the immune system to produce antigen-specific
humoral (antibody) and cellular immunity for which the protective function of
immunization is associated with cells. Usually this lasts for many years, and often for
a lifetime. One way to acquire active immunity is to survive infection with the disease-
causing form of the organism. Upon re-exposure to the same antigen, the memory cells
begin to replicate and produce antibody very rapidly to re-establish protection.
A safer way to produce active immunity is by vaccination. Vaccines interact with the
immune system and often produce an immune response similar to that produced by the
natural infection, but they do not subject the recipient to the disease and its potential
complications.
Many factors may influence the immune response to vaccination. These include the
presence of maternal antibody, nature and dose of antigen, route of administration,
and the presence of an adjuvant (e.g. aluminium-containing material) that is added
to improve the immunogenicity of the vaccine. Host factors such as age, nutritional
factors, genetics and coexisting disease may also affect the response.
3
September 2014
2.1.2 Passive immunity

Passive immunity is the transfer of antibody produced by a human or animal to another.
This may be natural (from mother to infant) or artificial1 (when high levels of human
antibodies specific to a pathogen or toxin are transferred to non-immune individuals)
The most common form of passive immunity is that which an infant receives from its
mother. The antibodies received from the mother protect the infant from certain diseases
for up to a year. However, maternal antibodies may inhibit successful immunization
against live or attenuated live viral vaccines by interfering with vaccine virus growth. For
example, vaccination with the live attenuated measles vaccine needs to be given at the
appropriate age (usually after 9 months of age) at which time the presence of maternal
antibodies (to measles) in the infants has fallen.
Passive artificial immunity provides only temporary protection against infection – as

short as 1-6 weeks – because the antibodies degrade over time.
2.1.3 Herd immunity

Herd immunity describes immunity that occurs when the vaccination of a portion of
the population (the “herd”) provides protection to unprotected individuals.2 Herd
immunity theory proposes that, in diseases passed from individual to individual, it is
difficult to maintain a chain of infection when large numbers of the population are
immune. Hence, the higher the proportion of immune individuals in a population, the
lower the likelihood that a susceptible person will come into contact with an infectious
agent. Both theoretically and practically, disease usually disappears before immunization
levels reach 100%, as has been seen with smallpox and is hoped will happen with
poliomyelitis. The proportion of immune individuals in a population above which a
disease may no longer persist is the “herd immunity threshold”. Its value varies with
the virulence and transmissibility of the disease, the efficacy and overall coverage of the
vaccine, vaccination coverage among the population at risk and the contact parameter
for the population.
2.1.4 How does immunization work?

There are several types of vaccines but they all work in a similar way, by preparing the
immune system to attack the infection. Each vaccine has components that are more or
less similar to the infecting organism or virus, and so the immune system responds as it
would to an infection with that particular organism. The most important consequence of
successful vaccination is that it produces long-lived memory lymphocytes that respond
more quickly and in a more coordinated way to subsequent infections. As a result, the
infectious microbe is destroyed more quickly. Protection is not always complete; an
infection might not always be prevented but the severity of the illness is usually reduced.
1
The history of vaccines. Philadelphia (PA): The College of Physicians of Philadelphia (http://www.historyofvac-
cines.org/content/articles/passive-immunization, accessed 1 August 2014).
2
Community immunity («herd Immunity»). Washington (DC): US Department of Health and Human Services
(http://www.vaccines.gov/basics/protection, accessed 1 August 2014).
4
The first exposure to a vaccine stimulates the immune response (known as priming).
The immune system takes time to respond to the antigen by producing antibodies and
immune cells. Initially, immunoglobulin M (IgM) antibody is produced but this occurs
in small amounts and does not bind very strongly to the antigen. After a few days, the
immune response begins to make immunoglobulin G (IgG) antibody which is more
specific to the microbe and lasts longer than IgM.
Subsequent administration of the same vaccine stimulates the secondary immune

response, which is much faster than the primary response and produces predominantly
IgG rather than IgM. The aim of vaccination is to generate enough immune cells and
antibodies specific to that vaccine-preventable microbe in order to provide long-lasting
protection against the disease.
2.2 Vaccines
A Vaccine is a biological product that produces and enhances immunity to a particular
VPD. A vaccine contains a disease-causing microorganism or virus, or a portion of it, and
is often made from either live attenuated or inactivated (killed) forms of the microbe, or
from its toxin or one of its surface proteins.
Vaccines may be monovalent or multivalent (or polyvalent). A monovalent vaccine

contains a single strain of a single antigen/immunogen (e.g. measles vaccine), whereas
a polyvalent vaccine contains two or more strains/serotypes of the same antigen/
immunogen (e.g. tOPV and IPV each of which contain three attenuated polio virus
types ).
Combined vaccines contain two or more different antigens (e.g. DTwP, DTPa-HepB-
Hib). The potential advantages of combination vaccines include reducing the cost of
storing and administering multiple vaccines simultaneously, reducing the cost of extra
health-care visits, improving timeliness of vaccination, and facilitating the addition of
new vaccines into immunization programmes.
There is no evidence that the administration of several antigens in combined vaccines

increases the burden on the immune system, which is capable of responding to millions
of antigens at a time.3 Combining antigens usually does not increase the risk of adverse
reactions and can lead to an overall reduction in adverse reactions.4 For instance, it
can decrease the number of anxiety-related reactions and the chances of immunization
error-related reactions.
Frequently asked questions about multiple vaccinations and the immune system. Atlanta (GA): Centers for
3
Disease Control and Prevention (http://www.cdc.gov/vaccinesafety/vaccines/multiplevaccines.html, accessed

1 August 2014).
4
Alberta immunization policy – general guidelines. Edmonton: Government of Alberta; 2014 (http://www.
health.alberta.ca/documents/AIP-General-Guidelines.pdf, accessed 1 August 2014).
5
September 2014
2.2.1 Classification of vaccines

There are different types of vaccines, such as: live attenuated, inactivated (killed antigen),
subunit (purified antigen) and toxoids (inactivated toxic compounds). The characteristics
of these vaccines differ, and these characteristics determine how the vaccines work
(Table 1).
2.2.1.1 Live attenuated vaccines
Live attenuated vaccines (LAVs) are derived, as are inactivated vaccines, from “wild”
or disease-causing viruses or bacteria. These wild viruses or bacteria are attenuated, or
weakened, in a laboratory, usually by repeated culturing. Live microorganisms provide
continuous antigenic stimulus, giving sufficient time for memory cell production in the
vaccinated person, and they are also capable of replicating within the host. The immune
response to a LAV is virtually identical to that produced by a natural infection.
Table 1. Classification of vaccines
Live attenuated Bacteria:

vaccines (LAV) BCG vaccine
Virus:
Live Japanese encephalitis vaccine, oral poliovirus vaccine,
measles vaccine, mumps vaccine, rotavirus vaccine, rubella
vaccine, yellow fever vaccine
Inactivated (killed Bacteria:
antigen) vaccines Whole -cell pertussis (wP)
Virus:
Inactivated Japanese encephalitis vaccine, inactivated poliovirus
vaccine (IPV)
Subunit vaccines Protein-based:
(purified antigens) Hepatitis B vaccine
Acellular pertussis (aP) vaccine
Polysaccharide:
Meningococcal polysaccharide vaccine
Pneumococcal polysaccharide vaccine
Typhoid Vi polysaccharide vaccine
Conjugate vaccine:
Haemophilus influenzae type b (Hib) conjugate vaccine, meningitis
A and B conjugate vaccine
Pneumococcal conjugate vaccines (PCV-7, PCV-10, PCV-13)
Vi conjugate vaccine
Toxoids Tetanus toxoid
Diphtheria toxoid
6
There are a few safety and stability concerns for LAVs, including the rare possibility of
attenuated pathogens reverting to their original form and causing disease, particularly
in individuals with compromised immune systems5 (e.g. HIV) or in cases of sustained
infection (BCG - local lymphadenitis), or immunization errors (reconstitution, cold chain).
The first dose of LAV usually provides protection. For instance, 82-95% of recipients
will respond to a single dose of measles vaccine at 9 months.6 The second dose is
given as an additional opportunity to induce immunity in those who did not respond to
the first dose, and with the second dose more than 95% of persons will be immune.
Immunity following live vaccines is long-lasting and booster doses are not necessary,
with the exception of OPV which requires multiple doses for seroconversion. LAVs are
labile and can be damaged or destroyed by heat and light. They must be handled and
stored carefully. Currently used LAVs include vaccines for influenza (intranasal), measles,
mumps, OPV, rotavirus, rubella, varicella and yellow fever. Live attenuated bacterial
vaccines include BCG and oral typhoid vaccine.
2.2.1.2 Inactivated (killed) vaccines
Inactivated vaccines are produced by growing viruses (e.g. poliomyelitis vaccine) or

bacteria (e.g. whole-cell pertussis vaccine) in a culture medium and then inactivating
them with heat or chemicals (usually with formaldehyde). Because they are not alive,
these viruses cannot grow in a vaccinated individual and therefore cannot cause the
disease, even in an immunodeficient person. Inactivated vaccines are generally safer than
LAVs, with no risk of inducing the disease. Unlike LAVs, inactivated vaccines are usually
not affected by circulating maternal antibodies and do induce an immune response in
an infant. They are often more stable than a LAV.
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 only 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 with little or no cell-
mediated immunity. Antibody titres against inactivated antigens diminish with time. As
a result, some inactivated vaccines may require periodic supplemental doses to increase,
or “boost”, antibody titres.
2.2.1.3 Subunit vaccines
The whole organism is grown in culture media and then is further processed to purify
only those components to be included in the vaccine. Subunit vaccines are categorized
in three groups: protein-based, polysaccharide and conjugate vaccines.
5
Global Advisory Committee on Vaccine Safety, 3–4 December 2009. Wkly Epidemiol Rec. 2010;85(5):29-36
(http://www.who.int/vaccine_safety/committee/reports/Dec_2009/en/index.html, accessed 1 August 2014).
6
Measles vaccines: WHO position paper. Wkly Epidemiol Rec. 2009;84(35):349–360 (http://www.who.int/
wer/2009/wer8435.pdf, accessed 1 August 2014).
7
September 2014
Protein-based vaccines
Subunit vaccines can be protein-based. For example, the hepatitis B vaccine is made by inserting
a segment of the hepatitis B virus gene into a yeast cell. The modified yeast cell produces large
amounts of hepatitis B surface antigen which is purified and harvested and used to produce the
vaccine. The recombinant hepatitis B vaccine antigen is identical to the natural hepatitis B surface
antigen but does not contain virus DNA and is unable to replicate and produce infection. Protein-
based subunit vaccines present an antigen to the immune system without viral particles.
Another protein-based vaccine is the acellular pertussis (aP) vaccine which contains inactivated
pertussis toxin (protein) and may contain one or more other pertussis components. The pertussis
toxin is detoxified either by chemical treatment or by molecular genetic techniques.
Polysaccharide vaccines
When infecting humans, some bacteria are protected by a polysaccharide (sugar) capsule that
helps the organism to evade the human defence systems, especially in infants and young children.
Polysaccharide vaccines provoke an immune response against this capsule; however, they are
not very immunogenic and induce only short-term immunity, particularly in infants and young
children. Examples of these vaccines are the meningococcal and pneumococcal polysaccharide
vaccines which contain the polysaccharide coats, or capsules, of encapsulated bacteria which are
purified and non-infectious.
Conjugated vaccines
Infants and young children do not sufficiently respond well to polysaccharide vaccines which
produce antibodies through a T-cell independent mechanism. If these polysaccharide antigens are
chemically linked (conjugated) to a protein that T-cells recognize, then the conjugated vaccines can
elicit strong immune responses and immune memory in young children. Haemophilus influenzae
type b (Hib)7, pneumococcal (PCV-7, PCV-10, PCV-13)8 and meningococcal A are conjugated
vaccines that are widely used provide longer protection, even among young children.
2.2.1.4 Toxoid vaccines
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. Toxoid vaccines are produced
by purifying the toxin and altering it chemically. While they are no longer toxic, the toxoid is still
capable of inducing a specific immune response that is protective against the effect of the toxin.
To increase immune response, toxoid is combined with an adjuvant (e.g. aluminium salts). Toxoids
are not highly immunogenic and require booster doses. They are stable, long-lasting and have a
good safety profile.9
7
WHO position paper on Haemophilus influenzae type b conjugate vaccines. Wkly Epidemiol Rec. 2006;81(47):445—
452 (http://www.who.int/immunization/topics/hib/en/, accessed 1 August 2014).
8
Pneumococcal conjugate vaccine for childhood immunization. WHO position paper. Wkly Epidemiol Rec.
2007;82(12):93–104 (http://www.who.int/wer/2007/wer8212/en/, accessed 1 August 2014).
9
Tetanus vaccine. WHO position paper. Wkly Epidemiol Rec. 2006;81(20):197–208 (http://www.who.int/wer/2006/
wer8120/en/, accessed 1 August 2014).
8
2.2.2 Other components of vaccines (excipients)
Adjuvants
Sometimes a substance is added to a vaccine to enhance the immune response by
degree and/or duration, thus making it possible to reduce the amount of antigen
(immunogen) per dose or the total number of doses needed to achieve immunity.
An adjuvant helps slow escape of the antigen from the injection site to lengthen the
duration of contact between the antigen and the immune system. The commonly-
used adjuvant is aluminium salts (aluminium potassium phosphate or aluminium
potassium sulfate) which primarily enhance the immune response to protein. They have
been shown to be safe over several decades of use. Oil-in-water emulsions (ASO3
and ASO4) have used as adjuvants in some vaccines developed in recent years. Rarely,
adjuvants may cause injection site reactions – including subcutaneous nodules, sterile
abscess, granulomatous inflammation and contact hypersensitivity – particularly if the
administration technique is wrong (e.g. subcutaneous). Adjuvant-containing vaccines
should be administered intramuscularly.
Antibiotics
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 (less than 0.000025
g). Persons who are known to be allergic to neomycin should be closely observed after
vaccination so that any allergic reaction can be treated at once. Neomycin allergy is very
rare.
Preservatives
These are chemicals (e.g. thiomersal, phenol derivatives) that are added to killed or
subunit vaccines in order to inactivate viruses, detoxify bacterial toxins, and prevent
serious secondary infections in multidose vials as a result of bacterial or fungal
contamination. Thiomersal, which contains ethyl-mercury, has been subject to intense
public scrutiny but there is no evidence of any toxicity from thiomersal in vaccines.10
(Formaldehyde, an inactivating agent, is used during the manufacturing process to

inactivate viruses and bacteria and detoxify toxins and is removed almost completely
during the purification process.)
Stabilizers
Stabilizers are used to help the vaccine maintain its effectiveness during storage. To
confirm product quality (antigenicity) or stability, compounds may be added to vaccines
to address problems with acidity, alkalinity (pH), stability and temperature.
Vaccine stability is essential, particularly if the cold chain is unreliable. Instability can
cause decreased infectivity of LAVs and loss of vaccine antigenicity. Bacterial vaccines
WHO Global vaccine safety webpage (http://www.who.int/vaccine_safety/committee/topics/thiomersal/en/,

10
accessed 22 August 2014).

9
September 2014
can become unstable due to hydrolysis and aggregation of protein and carbohydrate
molecules. Stabilizing agents include MgCl2, MgSO4, lactose-sorbitol and sorbitol-
gelatine.
Other components (excipients) are added to vaccines for different

KEY POINTS
purposes and some are removed in subsequent manufacturing

steps. However, minute traces may remain in the final product. The
amounts present are of consequence only to individuals who are
allergic to them.
2.3 Contraindications and precautions
A contraindication to vaccination is a rare characteristic in a recipient that increases the

risk of a serious adverse reaction. 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 are not contraindications, but are events or conditions that should be
considered in determining if the benefits of the vaccine outweigh the risks (especially if
the would-be recipient is immunocompromised or pregnant). Precautions stated in the
product labelling may sometimes be inappropriately interpreted as contraindications,
resulting in missed opportunities to vaccinate.
No evidence exists of risk to the foetus from vaccinating pregnant women with
inactivated virus, bacterial vaccines or toxoids. LAVs administered to a pregnant woman
pose a theoretical risk to the fetus. However, the benefits of vaccinating pregnant
women usually outweigh potential risks when the likelihood of disease exposure is
high, when infection would pose a risk to the mother or fetus, and when the vaccine is
unlikely to cause harm.11
The safety and effectiveness of vaccines in immunocompromised persons are

determined by the type of immunodeficiency and degree of immunosuppression.
Each immunocompromised person is different and presents unique considerations
with regard to immunization. There is a potential for serious illness and death if
immunocompromised persons are under-immunized, and every effort should be made
11
See: Immunization during pregnancy. Geneva: World Health Organization (http://www.who.int/vaccine_sa-
fety/committee/topics/influenza/pregnancy/Jun_2013/en/index.html, accessed 1 August 2014);
Guidelines for vaccinating pregnant women. Atlanta (GA): Centers for Disease Control and Prevention
(http://www.cdc.gov/vaccines/pubs/preg-guide.htm).
10
to ensure adequate protection through immunization. However, inappropriate use of

LAV can cause serious adverse events in some immunocompromised persons as a result
of uncontrolled replication of the vaccine virus or bacterium.12
Summary
Immunity is the body’s innate ability to protect itself against disease.There are two basic mechanisms
for acquiring immunity: active and passive.
n Active immunity can be either natural, following an infection, and can last a lifetime, or it can
be caused through vaccination and also lasts for a long period.
n Passive immunity can also be either natural or artificial. Both last for a relatively short period.
n Vaccine is a biological product that improves immunity to a given disease and is divided into
four types: live attenuated, inactivated (killed), subunit and toxoid vaccines.
n Excipients (antibiotics, and stabilizers) contained in vaccines can very rarely cause reactions.
n Knowledge of what a vaccine contains is important in safety surveillance.
Bibliography:
Plotkin S, Orenstein W, Offit P. Vaccines, sixth edition. Edinburgh: Elsevier/Saunders; 2013.
WHO has developed position papers for vaccines which are periodically reviewed and
updated. These position papers provide details of vaccines, including their safety profiles.
See: http://www.who.int/immunization/documents/positionpapers/en/index.html, accessed
1 August 2014.
Canadian immunization guide. Vaccination of specific populations. Ottawa: Public Health Agency of Canada
12
(http://www.phac-aspc.gc.ca/publicat/cig-gci/p03-07-eng.php, accessed 1 August 2014).

11
3 Adverse
following immunization
events
Vaccines used in national immunization programmes

are extremely safe and effective. Nevertheless, no
vaccine is perfectly safe and adverse reactions may
occur. In addition to the vaccines themselves, the
process of immunization is a potential source of an
adverse reaction.
An AEFI is 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. 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.
In 2012, the existing classification regarding cause-specific categorization of AEFI was

revised by the Council for International Organizations of Medical Sciences (CIOMS) and
WHO and a new categorization was introduced (Table 2).
Table 2. Cause-specific categorization of AEFI (CIOMS/WHO 2012)

Cause-specific type of Definition
AEFI
Vaccine product-related An AEFI that is caused or precipitated by a vaccine due to one or
reaction more of the inherent properties of the vaccine product.
Vaccine quality defect-related An AEFI that is caused or precipitated by a vaccine that is due to
reaction one or more quality defects of the vaccine product, including its
administration device as provided by the manufacturer.
Immunization error- An AEFI that is caused by inappropriate vaccine handling,

related reaction (formerly prescribing or administration and thus by its nature is
“programme error”) 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.
and anxiety.
Note: “Immunization” as used in these definitions means the use of a vaccine for the purpose of immunizing individuals. “Use” includes all
processes that occur after a vaccine product has left the manufacturing/packaging site – i.e. handling, prescribing and administration of the vaccine.
13
September 2014
3.1 Vaccine reactions

Based specifically on 1) cause and on 2) seriousness and frequency, vaccine reactions
may be grouped into two broad categories:
1. Cause-specific vaccine reactions:

n vaccine product-related reaction;
n vaccine quality defect-related reaction;
2. Vaccine reactions by seriousness and frequency:
n common or minor reactions;
n rare or serious reactions.
3.1.1 Cause-specific vaccine reactions
The new cause-specific categorization is important for decision-making about a vaccine

product since it clearly differentiates the types of possible reactions related to the
components of a vaccine.
The first, a vaccine product-related reaction, 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). However, it is important to note that, among certain high-risk individuals,
there is a higher probability of these rare vaccine product-related reactions which do not
occur in the majority of vaccinees.
The second reaction, a vaccine quality defect-related reaction, is a 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 agent (e.g.
wild polio virus) during the manufacturing process or contamination introduced during
the manufacturing process could cause the vaccine quality defect-related reactions. In
the early years of immunization programmes, some major vaccine quality defect-related
reaction incidents were reported. However, since the introduction of good manufacturing
practice (GMP) manufacturing defects are now very rare. Since vaccine manufacturers
have started following GMP, and NRAs have been strengthened, the potential risk of
such quality defects is now rare.
In 1955, after administration of inactivated polio vaccine manufactured by

CASE STUDY
Cutter Laboratories in the USA, 40 000 people developed abortive polio, 200
were permanently paralysed and 10 died. Investigations revealed that two
production pools of 12 000 doses contained live virus.
Cause: Vaccine quality defect-related reaction
See: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1383764/.
14
3.1.2 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).
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%
3.1.2.1 Common, minor vaccine reactions
The purpose of a vaccine is to induce immunity by causing the recipient’s immune system
to react to the vaccine antigens. Local site reaction, fever and systemic symptoms can
result as part of the immune response. In addition, some of the vaccine’s components
(e.g. adjuvant, stabilizers or preservatives) can lead to reactions. An effective and safe
vaccine produces the best possible immunity and reduces these reactions to a minimum.
The proportions of reaction occurrences likely to be observed with the most commonly
used vaccines are listed in Annex 1.
The occurrence of local reactions such as pain, swelling and/or redness at the injection
site varies by the type of antigen. For example, these local reactions are reported very
commonly (>10%) with whole-cell DTP, whereas for acellular DTP it is only a common
reaction with a frequency of 1-10%. BCG causes a specific local reaction which starts
as a papule (lump) two or more weeks after immunization, then becomes ulcerated and
heals after several months, leaving a scar. Keloid (thickened scar tissue) from the BCG
lesion is more common among African and Asian populations.
The occurrence of systemic reactions also varies by the type of antigen. Fever is a very
common (>10%) systemic reaction reported for most antigens. Other common systemic
reactions (e.g. irritability, malaise, loss of appetite) can also occur after many antigens, and
DTwP has more reports of these systemic reactions than DTaP. For LAVs such as measles/
MMR and OPV, the systemic reactions can occur from vaccine virus infection. Measles
vaccine can cause fever, rash and/or conjunctivitis but this is very mild compared to “wild”
measles. However, it can be serious, and even fatal, for severely immunocompromised
individuals. Vaccine reactions for mumps vaccine (parotitis, swollen parotid gland) and
rubella vaccine (joint pains and swollen lymph nodes) are uncommon and affect less
than 1% of children. Rubella vaccine commonly causes symptoms in adults, with 15%
suffering from joint pains. Systemic reactions from OPV are uncommon and affect less
than 1% of vaccinees with diarrhoea, headache and/or muscle pain.
15
September 2014
It is important to note that these vaccine reaction rates are an expected response to the
vaccine antigen. However, if the observed vaccine reaction rate is significantly higher
than the expected vaccine reaction rate for any vaccine, an investigation is needed to
explain this. (This is described later in chapters 6 and 7.)
3.1.2.2 Rare, more serious vaccine reactions
“Serious” and “severe” are often used as interchangeable terms but they are different.
An AEFI will be considered “serious” if it results in death, is life-threatening, requires
in-patient hospitalization or prolongation of existing hospitalization, results in persistent
or significant disability/incapacity, is a congenital anomaly/birth defect, or requires
intervention to prevent permanent impairment or damage. “Severe” is used to describe
the intensity of a specific event (as in mild, moderate or severe). The event itself, however,
may be of relatively minor medical significance. For example, fever is a common and
relatively minor medical event but, according to its severity, it may be graded as mild
fever or moderate fever. Anaphylaxis, on the other hand, is always a serious event and
life-threatening. Most of the rare and more serious vaccine reactions (e.g. seizures,
thrombocytopenia, hypotonic-hyporesponsive episodes (HHEs), persistent inconsolable
screaming) do not lead to long-term problems. Anaphylaxis, while potentially fatal, is
treatable. Although encephalopathy is included as a rare reaction to measles or DTP
vaccine, it is not certain that these vaccines in fact cause encephalopathy.13
3.1.3 Prevention and treatment of vaccine reactions
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.
Advice should be given to parents 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.
Antipyretic medicines, in a recommended dosage and schedule, can be given as
recommended by the prescriber (or manufacturer). For an 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 advise against overuse of paracetamol or any other antipyretic medicine as
overdosing may harm the vaccinee. 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.
Ray P, Hayward J, Michelson D, Lewis E, Schwalbe J, Black S et al. Encephalopathy after whole-cell pertussis
13
or measles vaccination. Lack of evidence for a causal association in a retrospective case–control study. The
Pediatric Infectious Disease Journal. 2006;25(9) (http://www.rima.org/web/medline_pdf/EncephalopathyAf-
terVaccination.pdf, accessed 1 August 2014).
16
Using local remedies for any serious vaccine reaction can risk the health and life of
the vaccinee 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.
Vaccine anaphylaxis is very rare. However, it is recommended that preparedness to
provide emergency treatment for anaphylaxis is necessary in all clinic settings. All
immunization providers need to be trained and develop competence in recognizing and
managing anaphylaxis. (See Section 9 for details.)
3.2 Immunization error-related reactions14

“Immunization” as used here means the use of a vaccine for the purpose of immunizing
individuals. “Use” includes all processes that occur after a vaccine product has left the
manufacturing/packaging site – i.e. handling, prescribing and administration of the
vaccine.
Immunization error-related reactions are preventable and they divert attention from the
benefit of the immunization programme (Table 4). The identification and correction of
these errors in a timely manner are, therefore, of great importance.
An immunization error-related reaction may sometimes lead to a cluster of events
associated with immunization. These clusters are usually linked to a particular provider or
health facility, or even to single or multiple vials of vaccine that have been contaminated
or inappropriately prepared. For instance, freezing vaccine during transport may lead to
an increase in local reactions.
In the past, the most common immunization error was an infection as a result of a non-
sterile injection because of contamination of the vaccine or diluent 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 bloodborne
infections. With the introduction of auto-disable (AD) syringes, such occurrences have
reduced significantly. Nevertheless, 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 programme 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.
Note: This AEFI type was earlier categorized as “programme error” (see Table 2)
14
17
September 2014
Table 4. Immunization error-related reactions
Immunization error Related reaction

Exposure to excess heat Systemic or local reactions due to changes
or cold as a result of in the physical nature of the vaccine, such
inappropriate transport, as agglutination of aluminium-based
storage or handling of the excipients in freeze-sensitive vaccines
vaccine (and its diluents
Error in vaccine
where applicable)
handling
Use of a product after the Failure to protect as a result of loss of

expiry date potency or nonviability of an attenuated
product
Error in vaccine Failure to adhere to a Anaphylaxis, disseminated infection with

prescribing or contraindication a LAV
non-adherence to
recommendations Failure to adhere to vaccine Systemic and/or local reactions,
for use indications or prescription neurological, muscular, vascular or bony
(dose or schedule) injury due to incorrect injection site,
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
the intended vaccine or diluent
Error in
administration
Incorrect sterile technique or Infection at/beyond the site of injection

inappropriate procedure with
a multidose vial
Sterile abscesses are rare (~1 per 100 000 doses) local reactions from aluminium-
containing vaccines, especially DTP. Inadequate shaking of the vaccine before use,
superficial injection and use of frozen vaccine increase the risk of sterile abscesses and
local reactions. Contamination of vaccine or injection equipment can also lead to a
bacterial abscess. For BCG vaccine, injection abscess can result from improper technique
of injection (subcutaneous rather than intradermal injection).
Ignoring contraindications can lead to serious vaccine reactions and is considered an
immunization error. The immunization team should be clearly aware of absolute and
relative contraindications. Any uncertainty should be referred to a higher level – a
programme 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.
Health-care workers also need a clear understanding of contraindications and precautions.
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. The vaccines
that are recommended in pregnancy will benefit and protect both mother and newborn.
18
However, the limited use of vaccination in pregnancy is largely due to the potential
risk of harm to the foetus. This risk is limited to LAVs which carry a theoretical risk of
infecting the foetus. Vaccine manufacturers mention pregnancy as a contraindication
on the package inserts not because of proven evidence of harm but as a precautionary
measure because there are few licensure studies of vaccination of pregnant women and
there is limited information on proven safety or harm to the foetus.
To avoid/minimize immunization error, the following should be noted:
n It is both important and necessary to maintain the cold chain at all levels.
n Vaccines must be reconstituted only with the diluents supplied by the manufacturer.
n Reconstituted vaccine should be used within six hours after reconstitution; it must
be discarded at the end of each immunization session and should never be retained.
n Other than vaccines, no other medicines or substances should be stored in the
refrigerator of the immunization centre.
n Immunization workers must be adequately trained and closely supervised to ensure
that proper procedures are followed.
n Careful epidemiological investigation of an AEFI is needed to pinpoint the cause and
to correct immunization practices.
n 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 found to be related
to cold chain issues). Continued monitoring and supportive supervision can help to
minimize these adverse events.
n In 1992, in a hospital in country A, five neonates collapsed a few minutes after

immunization with BCG. Four were resuscitated and one died. Muscle-relaxant
drugs were found in the refrigerator in which the vaccines were kept.
n Cause: Immunization error-related reaction. Use of muscle-relaxant instead of
diluent.
n In 2008–2009, in country B, during a school-based rubella immunization
programme, two 14 year-old girls collapsed within 15 minutes of immunization.
Prior to collapsing they developed generalized rash (urticaria or hives) and a
CASE STUDIES
persistent cough with wheeze.The incidents occurred in two separate places and at
different times. Both girls were hospitalized and later died. Investigation revealed
that both children had informed the immunization teams about their past history
of allergic reactions to some animal food products, but the immunization teams
ignored the history. Also there was no preparedness to manage anaphylaxis.
n Cause: Immunization error-related reaction. Lack of attention on a contraindication
and lack of preparedness to manage anaphylaxis.
n Vaccine product-related reaction. Anaphylaxis is a known reaction to rubella
vaccine. (Rubella vaccine used in this country has contained gelatine, and the link
between gelatine and red meat, leading to severe allergic reactions, is documented
in medical literature)
n In 1997, in country C, 21 infants died out of 70 infants supposedly given DTP
vaccine. Insulin was stored in similar vials and in the same refrigerator as the DTP
vaccine.
Cause: Immunization error-related reaction. Use of insulin instead of DTP.
19
September 2014
3.3 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 content of the vaccine.
Fainting (vasovagal syncope or syncope) is relatively common, particularly in children
over five years of age and among adolescents. Fainting does not require any clinical
management beyond placing the patient in a recumbent position. Some children who
faint may have a syncopal hypoxic convulsion. This is a short-lived generalized tonic-
clonic seizure. The management is to keep the child lying down and secure the airway
by placing the child in the “coma” position. 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.
Hyperventilation as a result of anxiety about the immunization leads to specific symptoms
such as light-headedness, dizziness, tingling around the mouth and in the hands. This is
also common in mass vaccination campaigns.
Younger children tend to react differently, with vomiting a common symptom of anxiety.
Breath-holding may also occur and can result in a brief period of unconsciousness during
which breathing resumes. Young children may also scream or run away to avoid the
injection.
These reactions are not related to the vaccine, but to the injection. Some individuals
may have needle-phobia, aggravating such reactions. In group immunization, mass
hysteria is possible, especially if a vaccinee is seen to faint or have some other reaction
such as itching, weakness of limbs and so on. Sometime, these cases 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.
It is important to note that a fainting episode can be misdiagnosed as anaphylaxis.
Health workers need to be able to differentiate between the two conditions. Careful
observation and clinical judgement is necessary. However, if by mistake a health-care
worker administers a single dose of adrenaline (intramuscularly) to a vaccinee with only
syncope, this does not harm the vaccinee. Therefore it is necessary to promote training
and awareness to enable health staff to identify and manage medical emergencies
appropriately (more details are outlined in Chapter 9).
Case study In 2004, a school-based mass measles-rubella immunization

CASE STUDY
campaign was conducted among young persons aged 12–19 years in country
D. On the first day, 44 children were hospitalized with hyperventilation or/
and vomiting. An investigation concluded that more than 90% of the cases
were anxiety reactions and all but two cases were discharged from hospital
the same day.
Cause: Immunization anxiety-related reactions.
20
3.4 Coincidental events
An event may occur coincidentally with immunization and sometimes be falsely

attributed to the vaccine. In other words, a chance temporal association (i.e. an event
happening after immunization) is falsely considered to be caused by immunization.
Such temporal associations are inevitable given the large number of vaccine doses
administered, especially in a mass immunization campaign.
Vaccines are normally administered early in life when infections and other illnesses are
common, including manifestations of underlying congenital or neurological conditions.
It is, therefore, possible to encounter many events, including deaths that can be falsely
attributed to vaccine through a chance association.
For instance, 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
studies15 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.
A similar calculation is shown in Table 5 for deaths of infants (aged under one year) in
selected countries for the number of deaths temporally associated with routine DTP
or pentavalent vaccine (PVV) immunization. There will be many coincidental deaths
in the day, week and month after immunization which are only temporally related to
immunization. The actual number of coincidental deaths depends on the population size,
infant mortality rate, number of immunization episodes and immunization coverage.
When comparing expected versus actual events, it is possible to use statistical analysis
to ensure that differences are not simply the result of chance. In general, coincidental
events which are clearly unrelated may still require investigation because certain serious
events may be blamed on the vaccine by parents, public or media due to the close
temporal association with immunization, especially if the child was previously healthy.
Such cases need to be investigated in order to allay public fear and maintain credibility.
Responding to public concerns about immunization safety is important in maintaining
confidence in the immunization programme. Availability of information on background
rates of reported coincidental events may be helpful in the investigation of an AEFI.
For current issues and SIDS, see the website of the American SIDS Institute (Naples, FL) at: http://sids.org/
15
category/news/ (accessed 1 August 2014). Also:

– Kuhnert R, Schlaud M, Poethko-Müller C, Vennemann M, Fleming P, Blair PS et al. Reanalyses of case-control
studies examining the temporal association between sudden infant death syndrome and vaccination. Vac-
cine. 2012;30(13):2349-56 (http://www.ncbi.nlm.nih.gov/pubmed/22289512, accessed 1 August 2014).
– Matturri L, Del Corno G, Lavezzi AM. Sudden infant death following hexavalent vaccination: a neuropatho-
logic study. Curr Med Chem. 2014;21(7):941-6 (http://www.ncbi.nlm.nih.gov/pubmed/24083600, accessed
1 August 2014).
21
September 2014
n In response to a severe diphtheria outbreak in country E in 1996, diphtheria-

tetanus vaccine was provided to children in a mass campaign. The death of
a seven-year-old girl, 2-3 days following immunization, was reported. The
symptoms reported included convulsions that might have been attributable to
a vaccine reaction. Upon investigation, it was found that the girl had a history of
convulsions and neurological symptoms unrelated to immunization and it was a
coincidental event.
CASE STUDIES
n In 2010, six infants died within 48 hours following administration of pentavalent

(DTP-HepB-Hib) vaccine in country F. Use of the vaccine was temporarily
suspended. A high-level investigation was carried out as the deaths had led to
public concern and health staff were reluctant to use the vaccine. Investigation
and assessment revealed that, out of six cases, three were confirmed as
coincidental. One was suffocation and two were due to underlying infections. Of
the other three cases, one was diagnosed as anaphylaxis and the other two were
inconclusive.
n In 2010, the death of a four-month old infant following DTwP vaccination was
reported in country G. Within a week, six more cases of severe local reactions
were reported with the same batch of DTwP, causing high public and media
attention. The implicated vaccine lot was temporarily suspended and replaced
with another lot, and a comprehensive investigation was carried out, including
toxicity and sterility-testing at national and WHO-accredited laboratories.
Causality assessment confirmed the death as coincidental, but six reported severe
local reactions were most likely due to immunization error-related reactions.
Table 5. Estimated number of coincidental infant deaths that could

be temporally linked to immunization (e.g. with DPT/PVV) in the
month, week and day after immunization in selected countries
Country Infant Number of Estimated number of Estimated number of PVV/DTP

mortality births per infant deaths in immunizations* in
Infant
rate per year
mortality
1000 live
rate per
births (N) a month a a a month a week a day
1000 live
(IMR) week day
births
(IMR)
Bhutan 42 15 000 53 12 2 3233 746 106
Canada 5 388 000 162 37 5 86 864 20 045 2856
China 3 634 035 838 624 119 475

13 16 364 000 17 728 4091 583
Indonesia 950 113 219 257 31 237

25 4 331 000 9023 2082 297
Iran 21 1 255 000 2196 507 72 276 445 63 795 9089
Mexico 13 2 195 000 2378 549 78 487 455 112 490 16 026
Sudan 313 382 72 319 10 303

57 1 477 000 7016 1619 231
United 170 540 39 355 5607

Kingdom 4 761 000 254 59 8
Note: Assumes uniform distribution of deaths and immunization over the time period.
Source: Infant mortality and births from 2011 immunization summary. New York (NY) and Geneva: United Nations Children’s Fund and World Health
Organization; 2013 (http://www.unicef.org/videoaudio/PDFs/EN-ImmSumm-2013.pdf, accessed 7 December 2013).
*The assumption here is a three-dose schedule for either DTP or PVV, with 90% coverage for each dose,
22
If the same or similar events affect others in the same age group around the same time
but those others did not receive the suspect vaccine(s), then a coincidental event is more
likely. There may also be evidence showing that the event is not related to immunization.
With increasing awareness of AEFI surveillance, even health staff may report more
coincidental events. Also, with the introduction of a new vaccine, there is a tendency to
report any AEFI, including coincidental events. It is crucial to differentiate these reported
coincidental events from potential signals.
Summary
n Vaccine adverse reactions may occur due to some inherent properties of the vaccine (vaccine
product-related reactions) or due to quality defects (vaccine quality defect-related reactions) or
due to immunization error-related reactions.
n At times, the event may be unrelated to immunization but may have a temporal association
with it (coincidental event).
n Immunization anxiety-related reactions are commoner, resulting from fear of, or pain due to,
injection rather than from the vaccine itself. In some cases, the cause of the AEFI remains
unknown.
n Immunization error-related reactions (previously classified as “programme errors”) are
avoidable.
n Antigen/vaccine-specific rates of vaccine reactions are useful to guide decision-making on
vaccine-related reactions
(http://www.who.int/vaccine_safety/initiative/tools/vaccinfosheets/en/index.html).
n Minor vaccine reactions are common and do not require special treatment. Rare, serious
vaccine reactions need timely treatment by qualified medical personnel.
Bibliography:
n Black S, Escola J, Siegrist CA, Halsey N, MacDonald N, Law B et al. Importance of
background rates of disease in assessment of vaccine safety during mass immunisation
with pandemic H1N1 influenza vaccines. Lancet. 2009;374(9707):2115-2122. doi:10.1016
%2FS0140-6736(09)61877-8.
n Duclos P, Bentsi-Enchill AD, Pfeifer D. Vaccine safety and adverse events: lessons
learnt. In: Kaufmann SHE, Lamert PH, editors. The grand challenge for the future. Basel:
Birkhäuser Verlag; 2005:209–29.
n Supplementary information on vaccine safety 2000. Geneva: World Health Organization;
2000 (WHO/V&B/00.24).
n WHO Vaccine-preventable diseases: monitoring system. 2009 global summary. Geneva:
World Health Organization; 2009 (WHO/IVB/2009).
n WHO has developed vaccine reaction information sheets for selected vaccines.
They comprise details of mild and severe adverse reactions (local and systemic)
following immunization. See: http://www.who.int/vaccine_safety/initiative/
tools/vaccinfosheets/en/index.html (accessed 1 August 2014). Expected rates
of vaccine reactions have been included, if available, in published literature.
23
4 Immunization
surveillance system
safety
Pharmacovigilance is the practice of detecting,

assessing, understanding, responding to and
preventing adverse drug reactions, including
reactions to vaccines.16 Pharmacovigilance is now an
integral part of the regulation of drug and vaccine
safety. While regulatory and public health agency
pharmacovigilance activities are equally robust for
medicines and vaccines, AEFI surveillance often relies
on different systems and procedures. Immunization
safety is the process of ensuring and monitoring
the safety of all aspects of immunization, including
the detection and investigation of adverse events,
vaccine quality, vaccine storage and handling, vaccine
administration, disposal of sharps and management
of waste.
4.1 Objectives
There are several potential objectives for establishing immunization safety surveillance.
Clearly stating and documenting the most important objective(s) of the system at the
time of establishing it will assist in designing both the system and its implementation.
The relative importance of the objectives will depend on the state of the immunization
programme and local circumstances. The objectives may change over time.
The major goal of immunization safety surveillance is early detection and analysis of
adverse events and appropriate and quick response in order to decrease the negative
impact on the health of individuals and the immunization programme.
In establishing immunization safety surveillance, the clear articulation of objectives

should generate the support of health workers and encourage them to report AEFI. If
resources are limited, prioritizing the objectives is recommended.
It is important that any information obtained through immunization safety surveillance

is rapidly assessed and analysed in order to identify problems and respond to them.
Response is a critical aspect of immunization safety surveillance.
Definition and application of terms for vaccine pharmacovigilance. Report of the CIOMS/WHO Working
16
Group on Vaccine Pharmacovigilance. Geneva: Council for International Organizations of Medical Sciences;
2012 (http://www.who.int/vaccine_safety/initiative/tools/CIOMS_report_WG_vaccine.pdf accessed 1 August
2014).
25
September 2014
Specific objectives of immunization safety surveillance
The specific objectives of immunization safety surveillance are:
n to detect and identify problems with vaccines which could be due to the inherent
properties of a vaccine or to defects in quality, and to detect, correct and prevent
immunization error-related reactions;
n to determine the observed vaccine reaction rate and relate this to the expected
vaccine reaction rates in the population by country, by region and globally;
n to ensure that coincidental events are not mistaken for vaccine reactions and thus
negatively affect the immunization programme;
n to ensure and facilitate causality assessment of individual AEFI reports (cases);
n to identify clustering or unusually high rates of AEFI, even if they are considered
mild;
n to identify events which may indicate a previously unknown and potential vaccine
reaction (i.e. a signal) and to generate new hypotheses about the causal relationship
between the event and the vaccine (this will then require further investigations to
support or refute the hypothesis);
n to maintain the confidence of the community and health staff in the immunization
programme by appropriate and timely responses to their concerns about
immunization safety;
n to create awareness on immunization safety among parents, community, the media
and other stakeholders without jeopardizing the immunization programme;
n to collaborate and share information with the regulatory authorities in order to
ensure vaccine safety;
n to ensure that channels of communication on AEFI between the NRA and the
immunization programme are clear and that information is provided regularly by
the unit responsible for immunization safety surveillance;
n to collaborate and share information with the WHO regional offices and globally in
order to generate additional information on vaccine safety.
4.2 Types of immunization safety surveillance
Passive surveillance: This encompasses all spontaneous AEFI reporting from

immunization service providers/hospitals/patients to the first administrative level (e.g.
divisional, municipality, township) in the surveillance system. From there, reports are sent
to the next reporting subnational level(s), ending at the national-level unit and global
institutions responsible for AEFI surveillance. 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
26
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: This is primarily used for characterization of the AEFI profile,
rates and risk factors, but logistical and resource constraints limit its wide application.
Countries may carry out active AEFI surveillance only for selected AEFI at selected
institutions (sentinel sites). Active surveillance can also be carried out in the community
setting (e.g. cohort event monitoring).
Ad hoc studies: Epidemiological studies (e.g. cohort study, case-control study, case
series studies) may be conducted in order to further expand immunization safety
surveillance activities. These studies are focused on selected vaccine safety concerns
(e.g. testing causality hypotheses).
In this manual, the focus is on routine Immunization safety i.e. passive surveillance
systems at subnational, national and international levels to ensure effective monitoring
and prompt action in response to AEFI. However, within or parallel to the spontaneous
reporting of a passive system, an active surveillance system can be established with
specific objectives for a specified time period. Immunization safety surveillance needs
to be a collaborative venture between the immunization programme and, when it
exists, the NRA, as both parties are responsible for the safety of vaccines. Depending
on the country’s administrative and operational structure, one unit/institution needs
to be the focal point for immunization safety surveillance. As the unit’s independence
is important, the task can be delegated to another organization or pharmacovigilance
centre (e.g. a university department) as long as the links with the NRA and the national
immunization programme are maintained. It is important to note that maintaining high
levels of transparency and independence are key factors which are necessary for building
and maintaining public trust in the AEFI surveillance system.
Immunization safety reporting systems should build on and mutually strengthen any
existing system of reporting information (e.g. immunization coverage reports, disease
incidence reports, and adverse drug reaction reports). The best AEFI reporting system is
the one which encourages a high level of appropriate reporting and takes timely action
in response to reports.
4.3 Steps for establishing an immunization safety surveillance

system
When developing an immunization safety surveillance system, countries are advised to

consider the following steps:
1. Clarify and agree on roles and responsibilities of both the immunization programme
and the NRA in immunization safety surveillance. It is important to designate an
institute to implement immunization safety surveillance. The roles and responsibilities
of the different categories of staff involved in immunization safety surveillance should
27
September 2014
be clearly identified. In countries where a pharmacovigilance centre is functioning,

the centre’s role and responsibilities in the immunization safety surveillance need to
be defined.
2. Develop a protocol with clearly defined objectives for immunization safety
surveillance, including strategies, structure, activities and resources.
3. Obtain legal provision for vaccine pharmacovigilance and government commitment.
4. Establish a national (central) expert committee for causality assessment and for
high-level technical support and decision-making. Large countries may have state or
provincial regional expert committees for similar purposes. Smaller countries where
such experts are not available can identify a supporting unit within the same region.
5. Develop and disseminate a list of events or criteria (see section 5.1) to be reported
(and investigated), their case definitions, standard investigation procedures and AEFI
reporting and investigation forms.
6. Ensure that staff are aware that monitoring and evaluation of activities are both
important and necessary. Train staff in reporting, data analysis, and investigation
and report preparation, according to the level at which each function is carried out.
7. Develop training materials and training modules suitable for the country’s
immunization and safety surveillance programme.
8. Develop a feedback system to update regularly the AEFI surveillance system (including
statistics, investigation findings, new developments).
9. Develop a communication plan to address concerns about, and information on,
immunization and safety surveillance.
10. Consider establishing a legal framework for a compensation scheme or social
support scheme, where applicable. If a legal framework is developed, ensure that it
is within the government’s health and/or social welfare policy.
Once the decisions about the safety surveillance system have been made, it is essential
to describe the structure of the system and the mechanisms for reporting. The system
will normally consist of the immunization service providers (in the public and private
sectors) who will provide reports on AEFI to the local health authority. Other than the
immunization service or health service provider at the periphery of the health system,
who may be in the private sector, all other key staff and structures for collation of
data, management of AEFI, and corrective action and feedback will usually be from
government bodies. Depending on a country’s administrative structure for health care,
there will normally be one or more intermediate levels between the immunization
service providers and the national immunization safety surveillance organization. The
intermediate levels report to the national level and the links between the NRA and the
immunization programme are usually at national level.
It is important to highlight that the functions described below for each stakeholder, or
stakeholder level, are only examples. Countries need to adopt their own modalities,
defining functions and respective responsibilities for each stakeholder or stakeholder
level.
28
4.4 Roles and responsibilities of the NRA in immunization safety

surveillance
NRAs are responsible for ensuring that any pharmaceutical product, including vaccines,
used within the country is (i) of good quality, (ii) effective, and (iii) safe for the purpose or
purposes for which it is proposed. While the first two criteria must be met before approval
of the vaccine’s medical use, the issue of safety is more challenging. Strengthening NRA
activities is necessary to ensure safe vaccine use and the monitoring of safety events in
the pre-licensure and post-marketing phases.
The immunization programme and NRA have a collective responsibility and play specific
roles in immunization safety surveillance. WHO has recommended that, in all vaccine-
producing countries and in all other countries where an NRA exists, the NRA must be
involved in immunization safety surveillance. WHO has defined six functions that should
be carried out by the NRA, as follows:
n marketing authorization and licensing activities, with clear written instructions for
licensing products and manufacturers;
n pharmacovigilance, including surveillance of AEFI;
n NRA lot release, with a system for lot release of vaccines;
n laboratory access, with use of laboratory when needed;
n regulatory inspection, with regular inspection of manufacturers for GMP compliance;
and
n regulatory oversight of clinical trials, with evaluation of clinical performance through
authorized clinical trials.
All countries should have some level of functioning NRA, but countries that produce
vaccines must exercise these six critical control functions (Table 6). The control functions
must be exercised in a transparent, technically competent and independent manner with
accountability and with the power to enforce changes that are considered necessary.
WHO carries out periodic assessment of the functions of NRAs in all countries, leading to
strengthened NRA functions over time. WHO has also published a manual for assessment
of the functions of national regulatory systems for vaccines.17 This assessment is carried
out by means of a tool specifically designed to assess regulatory systems in general and
the above six functions in particular. Performance indicators and sub-indicators have
been developed for each function. Some indicators and sub-indicators are “critical”
(i.e. it is mandatory for the NRA to achieve these indicators in order to qualify as being
fully functional. For pharmacovigilance surveillance of AEFI, there are seven indicators,
of which six are critical. Of the six functions, the licensure, marketing authorization
and vaccine pharmacovigilance functions are mandatory for all countries, irrespective of
whether they produce vaccines or not. Furthermore, WHO recommends that all countries
which do not produce vaccines must nevertheless define minimum specifications for the
vaccines they use. There should also be a system of post-marketing surveillance in place
17
Regulation and quality control of vaccines. Geneva: World Health Organization http://www.who.int/biologi-
cals/vaccines/regulation_and_quality_control_vaccines/en/, accessed 1 August 2014).
29
September 2014
to detect problems of vaccine performance. In all countries, AEFI should be monitored,

reported and investigated.
Table 6. Critical control functions of country NRA by vaccine

source
NRA functions
Vaccine
source for Marketing Pharamacovigilance Regulatory
country Lot Laboratory Clinical
authorization including and GMP
release access evaluation
and licensing surveillance inspection
United
Nations
agency X X . . .
Procured X X X X . .
Produced X X X X X X
The NRA’s contribution to, and responsibility for, investigation and appropriate follow-
up are part of the AEFI surveillance system in the country. For this purpose, there should
be close and clear communication and information-sharing between the NRA and the
immunization programme. The roles and modes of functioning of the two key players
need to be defined at the national level. Large countries, where NRA functions are
expanded to subnational levels, should clearly define the NRA roles and functions at
these levels.
4.5 Roles and responsibilities of the immunization programme

in immunization safety surveillance
An effective immunization safety surveillance system requires the involvement of

health workers at all levels of the immunization programme. This section identifies the
key players at different levels of the surveillance system and outlines their roles and
responsibilities in surveillance activities. These roles and responsibilities will depend on
the operational levels in different country settings.
It is assumed that a country should have three levels of immunization safety surveillance:
national (central), subnational or intermediate (state/province/region/district) and
service-provider level. In small countries, however, the surveillance may be limited to
two levels. When a country has three levels, functions and responsibilities are shared to
varying degrees between intermediate and national levels, depending on the country’s
size and the structure of its health-care system.
4.5.1 Roles and responsibilities at the level of the immunization service
provider
In these guidelines, the immunization service-provider level refers to the lowest

administrative level at which immunization services are provided to the public. Among
the tasks of immunization service providers are the following:
30
Detection of AEFI
Reporting of AEFI by the recipient, or by the parent or guardian of the recipient, should be
encouraged by clinics and hospitals. It is the responsibility of the clinic and hospital staff
to detect and report cases of AEFI. If treatment is necessary for a particular condition,
the child with an AEFI should be referred to the nearest hospital or health facility.
Recording of AEFI
The forms and registers necessary for immunization safety surveillance should be
supplied and maintained. All necessary data should be entered into the forms/records/
registers.
Reporting of AEFI
The next higher administrative/operational level should be immediately informed of all
serious events (including death) and/or unusual AEFI.
Other cases should be reported routinely, as instructed by the higher administrative/

operational level.
Investigation of AEFI
If the capacity to carry out an investigation exists, the investigation may be done at this
level. All investigations required for reported AEFI, as listed in the national guidelines,
need to be done as early as possible. Investigations should be appropriately supported
with laboratory-testing (See sections 6.6 and 6.7). Communication with the staff and
the community is essential. The public should be kept informed of what is being done
during the investigation and, once it is over, the conclusions and results should be shared
with other members of the team and the community. The findings of the investigation
should be shared with the service provider and should be submitted to the next higher
administrative/operational authority.
Corrective action
Corrective action, particularly in relation to immunization error-related events, should be
taken immediately on the basis of the findings of an investigation.
Analysis of AEFI data

It is recommended to keep line listing and detailed information separately. Depending
on the capacity of staff available, analysis may be limited to the basic variables.
Public education/communication
Whenever an opportunity is available, the public should be informed of what is being
done. People should be educated regarding AEFI.
4.5.2 Roles and responsibilities at the subnational level of immunization
services
The use of the term “subnational level” in these guidelines will vary according to the
administrative structure of a country’s health-care service. The term may refer to one
or more administrative levels in a country. Hence, “subnational level” represents all
31
September 2014
intermediate levels between the national level and the lowest administrative level in a
specific country.
(For instance, country A may have an administrative structure with four levels: national,
provincial, district and divisional. The provincial and district levels constitute the
intermediate levels in the country.)
Reporting of AEFI
The subnational level should inform the national level immediately of serious events
(including deaths) and/or unusual AEFI. Other cases should be reported routinely, as
stipulated by the national authority. All records on AEFI surveillance should be maintained.
All investigations required for reported AEFI, as listed in the national guidelines, need
to be carried out as early as possible. In most settings, the capacity to conduct a
comprehensive investigation is not available at the level of the immunization service
provider; therefore, collection of preliminary information on detailed investigations is
often the responsibility of the subnational (intermediate) level. It is therefore important
that countries invest effort in building capacity for AEFI investigation at the subnational
level. The findings of the investigation should be shared with the immunization service
provider and submitted to the authorities at national level.
Causality assessment
In large countries, where experts, expertise and resources are available, preliminary
causality assessment can be carried out at the subnational level and causality determined
for serious AEFI. However, AEFI cases with pending conclusions may be referred to the
national level for further evaluation and final classification.
Corrective and preventive actions

Both corrective and preventive actions should be taken as early as possible. However, such
actions should be based on the findings of the investigation. In practice, the subnational
level has the greatest responsibility for implementing corrective actions in terms of both
logistics and administration. For example, if any immunization error-related reactions
are observed, preventive actions such as strengthening supportive supervision, training
and even logistic replacements should be implemented by authorities at this level.
Analysis of AEFI
Analysis of data relevant to this level is necessary. Reports need to be produced on the
basis of the findings of data analyses and investigations.
Monitoring, supervision and training

Monitoring, supervision and training are key functions at this level. The authorities at this
level need to develop the capacity to carry out these functions efficiently and effectively.
Whenever necessary, the national level can assist subnational level with these activities,
including providing standard formats for supportive supervision, guidelines and training
materials.
32
Whenever an opportunity arises, the public should be informed of what is being done
and should be educated regarding AEFI.
4.5 3 Roles and responsibilities at the national level of immunization services
Investigation and causality assessment of AEFI

Investigations that require the services of national-level experts need to be prioritized (e.g.
serious cases, deaths, AEFI with public concerns). Causality assessment by the national
expert committee should be facilitated by all levels of the immunization programme, the
NRA and the government. If necessary, further research should be conducted to test a
hypothesis generated by the surveillance system/investigation.
Corrective and preventive actions

Both corrective and preventive actions should be taken as early as possible. However,
such actions should be based on the findings of the investigation. Vaccines should be
withdrawn or suspended only if available data are strongly supported by a causative
link to the vaccines. Preventive actions can lead to policy or/and programme strategy
changes.
Analysis and sharing of AEFI data

Reports should be produced on the findings of data analyses and investigations. AEFI
data must be shared periodically among all stakeholders responsible for the country’s
immunization programme, including immunization programme managers, the NRA and
NCL, academia and, when necessary, manufacturers and the public (Figure 1). Countries
are encouraged to share data regionally and globally through the WHO Programme for
International Drug Monitoring in order to generate additional and new information on
vaccine safety.
Feedback
Feedback is one of the most important elements of any surveillance system. Feedback
ensures and encourages reporting, which is the basis of AEFI surveillance, through the
continued interest of the staff at the subnational and service-delivery levels. In addition,
feedback is a learning process for the service-provider level and helps staff to improve
the immunization services. Weekly, monthly, quarterly and annual reports with statistics,
updates, new developments, findings of investigations and lessons learned are effective
means of feedback in AEFI surveillance.
Whenever there is a need, informing the public and media through special awareness
programmes is necessary. Developing a communication plan is also essential.
Monitoring, supervision and training

Staff awareness on AEFI should be assessed when monitoring and supervising
immunization services. Guidance and adequate training on AEFI surveillance and good
quality immunization practices should be provided to the staff. Whenever necessary, the
33
September 2014
staff must be re-trained. Training materials should be developed, with WHO support if
necessary.
Resource allocation
Sustainability depends on the availability of adequate resources at each level of the
surveillance system. Therefore, it is important that the national level (and possibly
subnational level) identify and allocate resources.
Note: National pharmacovigilance centres, which aim to ensure the safety of medicinal products, can play an active and important role in immunization
safety in their country. Advantages of pharmacovigilance centres are their independence and the availability of experts, especially where national
authorities need to strengthen collaboration in immunization safety activities.
Figure 1. Programme implementation level, responsibility and

surveillance activities
Administrative Responsabilities/Activities AEFI classification status

level
Health workers/Immunization service-provider level*

■ AEFI detection and recording Preliminary classification:
Peripheral ■ Triage and reporting of serious AEFIs to intermediate level ■ Non-serious
■ Routine reporting and line listing
level ■ Investigation
■ Serious
■ Corrective action
■ Public education / Communication
Surveillance units at sub-national level *

Provisional classification of serious
■ Support peripheral level AEFI
● Investigation of serious AEFI ■ For referral to national level
● Clinical and laboratory assessment ● Vaccine reaction
Intermediate ■ Causality Assessment of AEFI (preliminary) ● Coincidental
level ■ Report to national expert committee ● Unknown
■ Data analysis and search for additional cases ■ For local action
■ Corrective action ● Immunization error related
■ Monitoring and supervision/training ● Immunization anxiety related
■ Public education / Communication
National program (EPI/ NRA/ Supporting institutes

including National Pharmacovigilance centre)
■ Provide expert support for field investigation
■ Monitor information collection and assess serious AEFI Final classification of all serious AEFI
■ Causality Assessment of AEFI (Final - National AEFI
Maintain repository of all cases;
National committee) serious and non serious
■ Data analysis and search for signals
level ■ Recommend decisions for policy
■ Provide guidance on feedback to all levels
■ Conduct research studies
■ Provide guidance on Monitoring/supervision & training
■ Define contents for Public education / Communication
■ At global level share/ obtain expertise and assistance
4.5.4 Roles and responsibilities of immunization providers in the private sec-

tor
Case detection and reporting

The provision of health-care services in the private sector results in opportunities
for AEFI case detection and reporting. Individuals receiving vaccines at public-sector
immunization services could receive medical care for AEFI in the private sector. It is
therefore necessary to develop a link to report AEFI cases from the private sector to
the public health authorities. Several countries have integrated communicable disease
34
notification systems with reporting by both public and private sectors. It is proposed to
adopt a similar system to ensure reporting of AEFI from the private sector. The use of a
standard reporting form, incorporating a minimum set of co-variables recommended by
WHO, is advised.
Investigation is required for all AEFI reported from the private sector, as outlined in the
national guidelines. Public-private joint investigation is necessary when an AEFI is serious
or there is increased public concern. Findings need to be communicated to both the
immunization staff and the community.
Corrective action
In the private sector corrective action based on the findings of the investigation,
particularly regarding immunization errors, should be taken immediately as in the public
sector.
Immunization safety is the process of ensuring and monitoring the safety

of all aspects of immunization, including vaccine quality, adverse events,
vaccine storage and handling, vaccine administration, disposal of sharps
KEY POINTS
and management of waste.

n The AEFI surveillance system involves different stakeholders (the
immunization programme, the NRA and the NCL) and functions at
different levels from service delivery to national level.
n Feedback to all levels of the immunization and reporting system, and if
necessary to the public, is essential for building trust in the immunization
programme.
4.6 Terms of reference of the National Immunization Safety

Expert Committee
The Immunization Safety Expert Committee plays a critical role in confirming the causality
assessments of selected investigations and in determining causality when this has not
been established with confidence by the investigator.
Maintaining an active expert committee is a challenge. It is advised that only the most
critical cases – particularly those where causality needs to be assessed or those of public
or national concern – should be referred to this committee.
The committee should include a wide range of specialists whose expertise is important
in the reviewing of AEFI. Areas of expertise could include paediatrics, neurology, general
medicine, forensic medicine, pathology, microbiology, immunology and epidemiology.
Medical experts should be invited for the review of specific events. The committee needs
to be independent and have support from, and work in close communication with, both
the immunization programme and the NRA.
35
September 2014
The following generic terms of reference may be adapted by the National Immunization
Safety Expert Committee:
n assessing potential causal links between AEFI and a vaccine;

n monitoring reported AEFI data for potential signals of previously unrecognized
vaccine-related adverse events;
n reviewing all reported serious AEFI presented for expert opinion, making
arrangements to investigate further to establish causality, and making the necessary
recommendations to rectify problems (the expert committee may use the WHO
Aide-mémoire on causality assessment as resource material18 and is encouraged
to use in its investigations the comprehensive case definitions developed by the
Brighton Collaboration19);
n making final decisions on causality assessment following inconclusive investigations
and ensuring quality control of the immunization surveillance system;
n communicating with other national and international experts, when required, to
establish causality and to resolve vaccine quality issues;
n advising the national immunization programme (manager) and NRA on AEFI-related
issues when requested by these institutions; and
n advising the Ministry of Health on vaccine and immunization safety-related matters
when requested by the ministry.
Governance and function of the National Immunization Safety Expert Committee

Independence and transparency: Complete independence from government and
all industry-associated experts may not always be possible to achieve since it would
mean excluding much potential expertise. Therefore, the committee should discuss how
conflicts of interest/competing interests should be declared and decide which conflicts
may hinder an individual expert from taking part in the causality assessment of a specific
event for a given vaccine and which conflicts will not.
Role of the immunization programme and the NRA: Staff of both the immunization
programme and the NRA play a critical role. They should support the expert committee
and serve as the secretariat to facilitate the committee’s review (including preparing
documents for review). However, it is essential that they are uninvolved in decisions on
causality by the committee.
No industry participation: It is important to emphasize that employees of vaccine

manufacturing companies cannot be members of the expert committee. This is
because they will have conflicts of interest which could undermine the credibility and
acceptance of the committee’s conclusions. However, the committee may choose to
question company representatives if the industry is potentially the best source for certain
18
Aide-mémoire on causality assessment. Geneva: World Health Organization (http://www.who.int/vaccine_
safety/publications/AEFI_aide_memoire.pdf, accessed 1 August 2014).
19
Standardized case definitions for global use. Basel: Brighton Collaboration (https://brightoncollaboration.org/
public/what-we-do/setting-standards/case-definitions.html, accessed 1 August 2014).
36
information. For example, the committee might invite the industry to describe a specific
production process in one of their meetings.
4.7 Monitoring and evaluating the immunization safety

surveillance system
The immunization safety surveillance system should be continuously monitored and

also regularly evaluated. The purpose is to identify gaps and rectify them in order to
strengthen the immunization safety surveillance system in the country. The evaluation
should be based on performance, quality and responses:
1. To monitor the performance of the AEFI surveillance system:

a. AEFI reporting rate per 100 000 population
b. AEFI reporting rate per 100 000 < 5 population
c. AEFI reporting rate per 1 000 000 distributed doses of vaccines
d. AEFI reporting rate per 1 000 000 administered doses of vaccines
e. percentage of serious AEFI cases versus total AEFI reports;
2. To monitor the quality of AEFI reporting:

f. completeness of reports (% of AEFI report forms with completed
critical information)
g. timeliness of reports (% of serious AEFI reports received as per
specified time);
3. To monitor the response to serious AEFI:

h. timeliness of case investigation (% of serious AEFI cases investigated
within 48 hours of occurrence).
Note:At present, theWHO working group is developing more specific indicators. Once the indicators are finalized, they will be incorporated into this manual.
Annual data reports should include:

n The number of AEFI reports, categorized by type of reaction and
KEY NOTE
vaccine(s) and causality assessment (with denominator data on the

number of doses of vaccine given);
n the rate of each adverse event by vaccine nationally and by region;
n unusual or unusually severe events or large clusters; and
n summary findings of important investigations and lessons learned.
Making the annual report available to health workers encourages their reporting
and provides positive feedback on it. Publication of the data also allows international
comparisons to be made.
37
September 2014
4.8 Differences between surveillance of AEFI and adverse events

linked to other medical products
Vaccines are administered to healthy people for the prevention of disease while most
medicines are used to treat or control disease in sick people. Thus, a much higher level of
risk is acceptable for a medicine compared to a vaccine. An involuntary risk is perceived
as greater than a risk taken voluntarily. This fact reduces tolerance of AEFI if there is an
element of compulsion in the immunization programme. Further, vaccines are given
mainly to infants, and the large number of doses given (particularly in immunization
campaigns) lead to particular public concern or sensitivity about vaccines. Also, unlike
medicines (except for public health programmes such as de-worming, malaria and
vitamin supplementation), vaccines are administered not only for the benefit of the
individual but also for the benefit of the community. Hence AEFI, unlike adverse drug
reactions, may be perceived as being the responsibility of the community.
These differences do not preclude a monitoring system for adverse drug reactions
being used to monitor AEFI. However, the system must be sensitive to the specificity
of vaccines. Further, in many countries with a single monitoring system, surveillance of
AEFI is often overlooked. Different reporting pathways and responses to AEFI need to
be built into the existing system of surveillance for adverse drug reactions if the system’s
resources are to be shared.
The reporting pathways for the immunization programme may not be part of the usual
reporting trails for medicines and the most efficient way to collect to the reporting
of many coincidental events which are only temporally related to immunization, and
which require specific domain knowledge for comprehensive investigation and correct
interpretation. The priority for immunization safety surveillance is to identify and correct
immunization error-related events (particularly in resource-poor countries) and to
minimize other possible AEFI, including vaccine adverse reactions (Table 7).
The implication of an adverse event is quite different in scale for a vaccine which is given
to an entire cohort of the population, compared with a medicine exclusively used for
therapeutic purposes in a relatively smaller number of individuals. Hence, response and
communication about AEFI are likely to be both more important to the health of the
population, of greater interest, and more challenging.
38
Table 7. Checklist for the immunization safety surveillance system
CHECKLIST FOR THE IMMUNIZATION SAFETY SURVEILLANCE SYSTEM
1. Be prepared
n Clarify the respective roles of the NRA and the immunization programme, and agree on
the overall goal and specific objectives of the system.
n Identify the resources available and needed, and establish political commitment to im-
munization safety surveillance.
n Appoint or designate regional/national assessors for immunization safety.
n Establish an expert regional/national immunization safety committee.
n Develop and disseminate a list of events to be reported, their case definitions, a standard
investigation procedure, and AEFI reporting and investigation forms.
n Designate and train staff (at all levels) to make reports, complete report forms and investi-
gate AEFI.
�n Inform all health workers/clinicians of the need to report immediately an AEFI, and indicate
which ones should be reported.
n Consider the establishment of a compensation scheme for specified AEFI.
2. Receive a report (investigating authority)

n Decide if the report is a genuine AEFI according to the definition, and whether investiga-
tion and/or advice to the public/media are needed.
n Travel to the location of the AEFI, or delegate responsibility to another trained person or
team.
n Decide if there is a need to communicate with the community and/or media to alleviate
concerns.
3. Investigate and collect data

n Ask about the patient, the event and the vaccine.
n Ask about the immunization service and observe it in action (emphasize that the aim is to
find system errors, not to blame an individual).
n Formulate a working hypothesis regarding the cause of the AEFI.
n If appropriate, collect and dispatch specimens to the laboratory.
4. Analyse the data

n Review on-site investigation, clinical findings and laboratory results (if sent).
n Review epidemiological findings (e.g. clustering of cases in time or space or by vaccine
manufacturer or lot).
n Summarize findings and complete the investigation form.
5.Feedback
n Provide periodical (weekly/monthly/quarterly) feedback to operational levels of the health
system and also to other stakeholders
n Feedback could be in the form of newsletters, bulletins or special notes. In special events,
verbal feedback is encouraged.
39
September 2014
6. Follow-up action
n Communicate with health staff (e.g. treatment, information and stakeholders).
n Communicate findings and action to the parents and public (and media).
n Correct the problem (based on the cause) by improving training, supervision, and/or distri-
bution of vaccines/injection equipment.
7. Evaluation
n Evaluating the immunization safety surveillance system is necessary to monitor its impact
on vaccine safety and on the national immunization programme
n The country should develop evaluation indicators to monitor the surveillance system
Summary
n Immunization safety surveillance should be a collaborative venture between the immunization
programme and, when it exists, the NRA, because both parties are responsible for the safety
of vaccines. In countries where they are functioning, pharmacovigilance centres should also be
part of the country’s system of immunization safety surveillance.
n It is important to set clear objectives and follow each step to establish surveillance.
n Identifying clear roles and responsibilities of different stakeholders at different levels is
necessary to achieve functioning immunization safety surveillance in a country.
n To ensure capacity among vaccination staff, immunization officers and the immunization safety
expert committee, training should be undertaken at the country level, supported by international
resources, such as the Global Vaccine Safety Initiative training materials.
n There are three criteria for evaluating the performance of the immunization safety surveillance
programme: (i) AEFI reporting rates, (ii) quality of information and (iii) audit of response to AEFI.
Bibliography:
n Aide-mémoire: strengthening national regulatory authorities. Geneva: World Health
Organization (http://who.int/immunization/topics/nra_aidememoire_2003.pdf,
accessed 31 July 2013.
n Chen RT, Glasser J, Rhodes P, Davis RL, Barlow WE, Thompson RS et al. Vaccine Safety
Datalink project: a new tool for improving vaccine safety monitoring in the United
States. Pediatrics. 1997: 99(6):765–73.
n Definition and application of terms for vaccine pharmacovigilance. Report of CIOMS/
WHO Working Group on Vaccine Pharmacovigilance. Geneva: Council for International
Organizations of Medical Services; 2012 (http://www.who.int/vaccine_safety/initiative/
tools/CIOMS_report_WG_vaccine.pdf, accessed 1 August 2014).
n Davis RL, Kolczak M, Lewis E, Nordin J, Goodman M, Shay DK et al. Active surveillance
of vaccine safety: a system to detect early signs of adverse events. Epidemiology.
2005;16(3): 336–41.
n Duclos P. A global perspective on vaccine safety. Vaccine. 2004;22:2059–63.
n Duclos P, Bentsi-Enchill A. Current thoughts on the risks and benefits of immunization.
Drug Safety. 1993;8:404–13.
n Editorial. The development of standard case definitions and guidelines for adverse
events following immunization. Vaccine. 2007;25:5671–4.
40
n Surveillance of adverse events following immunization. Geneva: World Health

Organization; 1997 (WHO/EPI/TRAM/93.02REV.1; http://www.measlesrubellainitiative.
org/wp-content/uploads/2013/06/Surveillance-for-AEFI-Field-Guide.pdf, accessed 31
July 2014).
n Pless R, Duclos P. Reinforcing surveillance for vaccine-associated adverse events: the
Advisory Committee on Causality Assessment. Can J Infect Dis. 1996;7:98–9.
n The Brighton Collaboration has developed standardized, widely-disseminated and
globally-accepted case definitions and associated guidelines for the purpose of
enhancing data comparability within and across clinical trials, surveillance systems
and post-licensure clinical studies. The case definitions are designed to define the
levels of diagnostic certainty of reported AEFI. See: https://brightoncollaboration.org/
public/what-we-do/setting-standards/case-definitions.html, accessed 31 July 2014.
n General recommendations on immunization. Recommendations of the Advisory
Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report.
2011;60(No.RR-02):1–60 (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6002a1.htm,
41
5 Reporting AEFI
Case detection is the first important step in AEFI
surveillance. The primary reporter (i.e. the one who
first reports an AEFI) may be a field health worker,
clinic or hospital staff, a volunteer, parent or any other
person who detects the AEFI.
Suspicion alone is sufficient for reporting, and the

primary reporter is not expected to assess causality.
Rapid detection and evaluation of a possible link to
vaccines is essential to ensure the continued safety
of vaccines. Thus, in case of a suspected AEFI, it is
preferable to submit a report to a suitable technical
authority on time rather than waiting for all aspects of
an investigation to be completed. This is particularly
true for serious reports. In many settings the primary
reporter submits a report to the immediate reporting
authority which is generally a local public health
authority. The report is then transferred up through the intermediate level to the national
level, and to the central immunization programme and/or NRA. The reporters at different
levels may seek to clarify or request additional information before sending the report
onward. This chain of movement varies according to the government structure.
To improve detection, the primary reporting level should have a good knowledge of AEFI
types and the purpose of AEFI surveillance. Regular orientation, training and awareness
programmes are necessary to update knowledge and maintain enthusiasm among
primary reporters.
5.1 Which events should be reported?
Any AEFI that is of concern to parents or health-care workers should be reported. In

particular, health workers must report:
n serious AEFI;
n signals and events associated with a newly introduced vaccine;
n AEFI that may have been caused by an immunization error;
n significant events of unexplained cause occurring within 30 days after vaccination;
and
n events causing significant parental or community concern.
Reporting all minor AEFI such as high fever and minor local reactions is optional. These
are expected vaccine reactions and, if reported, the volume of reports would overwhelm
the system with information of limited value. However, it is helpful to monitor and
record crude numbers and compare them with background rates that could identify
43
September 2014
product quality defects, immunization errors or even increased susceptibility of vaccine

reactions among a particular population.
Table 8. List of examples of reportable AEFI

Reportable AEFI Time onset following immunization*
§ Acute flaccid paralysis for OPV recipient § 4-30 days following immunization
§ Acute flaccid paralysis for contact of OPV recipient § 4-75 days following immunization
Anaphylaxis (after any vaccine) Within 48 hours of immunization
Brachial neuritis (after tetanus-containing vaccine) 2-28 days following immunization
Disseminated BCG infection after BCG vaccine Between 1 and 12 months
Encephalopathy
§ after measles/MMR vaccine § 6-12 days following immunization
§ after DTP vaccine § 0-2 days following immunization
Hypotonic hyporesponsive episode (HHE) after DTP/PVV Median time is 3-4 hours after immunization, but ranges
vaccine from immediate to 48 hours. However, it can occur even
after 48 hours
Injection site abscess (bacterial/sterile) after any injectable Not specific. However, commonly within first 14 days of
vaccine immunization
Intussusception (after rotavirus vaccines) Commonly within 21 days, risk increased after the first 7
days and usually first dose
§ Lymphadenitis after BCG vaccine Between 1 and 12 months

§ Osteitis/osteomyelitis after BCG vaccine
Persistent (more than 3 hours) inconsolable screaming after Common immediately and up to 48 hours of immuniza-
DTP/PVV vaccine tion. However, it can occur even after 48 hours
Sepsis (after any injectable vaccine) Within 7 days following immunization
Seizures, including febrile seizures
after measles/MMR 6-12 days following immunization
after DTP/PVV 0-2 days following immunization
Severe local reaction (after any injectable vaccine) Within 7 days following immunization
Thrombocytopaenia (after measles/MMR) Median time is 12-25 days after immunization, but the
range is 1-83 days
Toxic shock syndrome (TSS) (after any injectable vaccine) Commonly within 72 hours following immunization
Death No time limit, but in general those within 30 days follow-

ing any immunization
Hospitalization
Disability
Any other severe and unusual events that are attributed to

immunization by health workers or the public
* The time interval to onset will depend on the antigen and the adverse reaction. For detailed information on antigen or adverse reaction-specific onset
intervals, refer to the Brighton Collaboration case definitions (https://brightoncollaboration.org/public/what-we-do/setting-standards/case-definitions.html),
WHO position papers and observed rates information sheets (http://www.who.int/vaccine_safety/initiative/tools/vaccinfosheets/en/index.html, accessed 1
August 2014).
44
A list of suggested reportable events is presented in Table 8. Each country should decide
which events are appropriate for inclusion in its reporting system. However, countries are
encouraged to include a broad range of events in order to increase global harmonization
of AEFI data.
It is important to note that the time interval between immunization and onset of the
event may not always be precise or well established. Consequently, the inclusion of time
interval in surveillance case definitions is reserved only for selected adverse reactions. It
is recommended that surveillance case definitions should be simple. The case definitions
developed by the Brighton Collaboration have different levels of diagnostic certainty
and are used widely. However, if countries have difficulty in adapting them to their local
situations, they can adopt their own valid surveillance case definitions for reporting
purposes.
Local reactions occurring at increased frequency, even if not severe, should also be
reported. These may be markers for immunization errors or for problems with specific
vaccine lots.
5.2 When to report?
Immediately. A report must be made as quickly as possible so that an immediate decision

can be made on the need for action and investigation. For incidents with many cases or
a high level of community concern, an urgent telephone call/fax/email to the decision-
making administrative/operational level is appropriate.
5.3 How to report?
Reports should be made on a standard AEFI reporting form.20 Annex 2 provides an

example of such a form. It is the responsibility of the immunization service provision unit
to supply these forms. The report should be kept simple but should ensure that health
workers can input essential information.
It is important that all of the minimum required information should be entered into
the reporting form, as this is the basis for decisions regarding the need for further
investigation. Countries are strongly encouraged to maintain at least the minimum
required information, so that data can be shared with regional and global partners
through the WHO Programme for International Drug Monitoring.
For optimal vaccine safety monitoring and meaningful analysis of AEFI data, systematic
and standard collection of critical parameters is essential. A limited number of variables
are required to manage AEFI information properly. These include a unique identifier
for the report, the primary source of information, patient characteristics, details of the
event(s), vaccine(s) of interest, and the possibility of collecting additional information if
needed. Any additional information that is collected would be useful for investigation.
20
Reporting form for adverse events following immunization (AEFI). Geneva: World Health Organization
(http://www.who.int/vaccine_safety/REPORTING_FORM_FOR_ADVERSE_EVENTS_FOLLOWING_IMMUNIZA-
TION.pdf, revised December 2015).
45
September 2014
A WHO working group developed a core data set that includes 25 variables21 (Table 9).
This simple structure provides a harmonized template that simplifies AEFI reporting and
allows for comparisons and pooling of essential information for action.
Table 9. Core variables with minimum information required for

reporting in AEFI surveillance
Suggested Heading Description of the Basic core variable

Date AEFI report first received at National level Date when information of the AEFI case first reached the National level
Identify
Country where the AEFI occurred Name of the country where the adverse event occurred
Location (address) Geographic location of the case (address)
Unique identification of the report Unique id number used for communicating the details of the case
Patient identifier Name of the patient or initials as decided by the country
Date of birth (or) Date patient was born
Age at time of onset (or) Age at time of onset

Case
Age Group at onset Age Group (<1 year, 1-5years, >5 years)
Sex Male or Female
Medical history Free text information (e.g. allergies, concomitant medication etc.)
Primary suspect vaccine name Vaccine suspected to have caused the AEFI
Vaccine
Other vaccines given just prior to AEFI Other vaccines given prior to the AEFI
Vaccine batch/lot number Batch/lot number of all vaccines mentioned above
Vaccine dose number for the vaccinee Dose number for this particular vaccinee
Diluent batch/lot number Batch/lot number of the diluent (if applicable)
Date and Time of vaccination Date and time the vaccine was administered
Date and Time of AEFI onset Date and time of the AEFI onset
Adverse event Case diagnosis + Signs & Symptoms
Event
Outcome of the reaction(s): Recovering/resolving; Recovered/resolved;

Outcome of AEFI Recovered/resolved with sequelae; Not recovered/not resolved; Fatal;
Unknown
If the case is serious and resulted in death, threatened the patient’s life, caused
persistent or significant disability, hospitalization, congenital anomaly or any
Serious case
other medically relevant event that may jeopardize the patient or may require
intervention to prevent one of the outcomes mentioned here
Name of initial reporter of AEFI case Name of the reporter of the AEFI case
Institution/Location Place (address) of the reporter (including the name of the country)
Reporter
Position/Department Reporter’s designation & section of work
E-mail address Reporter’s e-mail address
Telephone Reporter’s phone number
Date of report Date when the report was compiled by the reporter
Other
Additional details about the case in free text (including documents/

Comments (if any)
attachments)
IMPORTANT: Critical variables in italics
21
AEFI core variables. Geneva: World Health Organization (http://www.who.int/vaccine_safety/AEFI_Core_Va-
riables.pdf, revised December 2015).
46
If signals are detected, or in serious cases, additional data are essential to determine
the association of the event with the vaccine. An additional 33 variables of interest
have been developed for more detailed case review. It is proposed that reporting tools
used by countries should include a dictionary to standardize the terminology used to
record signs, symptoms or diagnosis, and a vaccine dictionary in order to identify sus-
pected vaccine at national or global levels.
Any AEFI that is of concern to parents or to the health-care

KEY POINTS
worker should be reported.

n Collection of harmonized data on AEFI allows for better comparison and
pooled analysis with findings from vaccine safety surveillance systems.
Therefore, it is recommended that countries incorporate a minimum set
of 25 core variables in their reporting form, making the form useful both
in the country itself and globally.
5.4 Reporting AEFI 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 to
respond to AEFI can minimize adverse events and their effects during an immunization
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:
n 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 may also affect
the immunization programme.
n 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. For example, cases of intussusception were reported
following the introduction of a new oral rotavirus vaccine (Rotashield) in the USA in
1998-1999.22
22
Murphy TV, Gargiullo PM, Massoudi MS et al. Intussusception among infants given an oral rotavirus vaccine.
N Engl J Med. 2001;344:564−572. doi:10.1056/NEJM200102223440804.
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September 2014
5.5 Barriers to reporting
Immunization service providers may not report AEFI for a number of reasons, such as:
n considering that the event did not occur after immunization (however, all events
following immunization as per the definition should be reported);
n lack of knowledge about the reporting system and process;
n apathy, procrastination, lack of interest or time, inability to find the reporting form;
n fear that the report will lead to personal consequences;
n guilt about having caused harm and being held responsible for the event; and
n diffidence about reporting an event when not confident about the diagnosis.
It is worth emphasizing that, unless immunization service providers/units at community
level generate and process reports appropriately, an adequate immunization safety
surveillance system will not exist. Staff must be encouraged to report adverse events
without fear of penalty. The aim is to improve systems or provide further training, and
not to blame individuals.
Positive feedback to health workers is essential. The feedback should include the
outcome of investigations or causality assessment when these are carried out, and
recommendations on the management of the vaccinee, particularly with regard to the
need for future vaccination.
There must be an adequate supply of reporting forms. Pre-addressed and postage-paid

forms may improve reporting in some countries, especially from private physicians.
5.6 Private-sector reporting
As in government institutions, all private-sector medical institutions handling

immunization services and treating AEFI cases should report all AEFI to the respective
immunization safety surveillance focal points or national pharmacovigilance centres.
Reporting from the private sector is encouraged for two reasons:
n Individuals seek medical care from the private sector, following vaccines received at
public institutions.
n It is important to monitor vaccines used in the private sector and, therefore, reporting
all AEFI is necessary.
To maintain uniformity of reporting data, AEFI reporting forms used in the AEFI
surveillance system should be made available to the private sector as well.
5.7 Vaccine Adverse Events Information Management System

(VAEIMS)
The VAEIMS is a software that has been developed by the International Vaccine Institute
in collaboration with WHO. The purpose of the software is to transfer AEFI data using
the core variables from the periphery of a health-care system, efficiently and effectively,
48
into a central database for processing and conversion into information that can guide
actions. The design of VAEIMS takes account of the diverse systems of data collection,
collation, transmission, analysis and feedback in different countries. It is tailor-made to
local conditions, and is able to provide quick and reliable information to decision-makers
at different levels in a country, and to a global audience.
VAEIMS allows the transfer of data from the each national database to Vigibase
(the global database) as it is E2B-compatible (ICH guideline on electronic reporting
of adverse events) for global sharing of AEFI data. The web-based version or offline
version of VAEIMS is available to all countries free of charge. The features of the web-
based VAEIMS include “live” data upload, data-sharing and analysis. At a later phase of
development of VAEIMS, the reporting of AEFI from the periphery to the national level
will be facilitated by making it possible to collect data using mobile telephones.
Summary
n A list of AEFI to be reported should be made available.
n Case definitions (e.g. by Brighton Collaboration) for each reportable event should be made
available.
n AEFI reporting should be made on standardized reporting forms using a minimum set of core
variables in order to make the global evaluation of signals possible and thus benefit countries
in their evaluations of AEFI.
n Private-sector reporting is encouraged.
n Sharing reports regionally and globally (via the WHO Programme for International Drug
Monitoring /UMC) is encouraged.
n Identifying barriers to reporting and taking appropriate action to address these barriers will
improve reporting.
Bibliography:
n Rosenthal S, Chen RT. Reporting sensitivities of two passive surveillance systems for
vaccine adverse events. Am J Public Health. 1995;85:1706–9.
n Varricchio F, Iskander J, Destefano F et al. Understanding vaccine safety information
from the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J. 2004;23(4):287–
94.
n Zhou W, Pool V, Iskander JK et al. Surveillance for safety after immunization: Vaccine
Adverse Event Reporting System (VAERS) – United States, 1991-2001. Morbidity and
Mortality Weekly Report. 2003;52(ss01):1–24.
n ICH efficacy guidelines. Geneva: International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human Use (http://
www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html, accessed 23
August 2014).
n Pharmacovigillance and drug safety for the UK and Europe (blog) (http://www.
pharmacovigilance.org.uk/tag/e2b/, accessed 23 August 2014).
49
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50
6 Investigating AEFI
6.1 Why AEFI reports
investigated
should be
The ultimate goal of a case investigation is to find the

cause of an AEFI and to implement follow-up actions.
Investigation should identify any immunization
error-related or vaccine product-related reactions
because these are preventable. If coincidental events
are recognized, proving them will be important to
maintain public confidence in the immunization
programme.
The purposes of investigating an AEFI case are the

following:
n to identify the details of vaccine(s) administered

and to determine the timing between
administration of the vaccine and the onset of the event;
n to confirm the reported diagnosis or establish a diagnosis;
n to document the outcome of the reported adverse event;
n to identify the cause of the AEFI;
n to determine whether a reported event is a single incident or one of a cluster and,
if it is part of a cluster, where the suspected immunizations were given and what
vaccines were used;
n to examine the operational aspects of the programme (even if an event seems to be
vaccine-induced or coincidental, immunization-related errors may have increased its
severity) and to prevent immunization-related errors;
n to determine whether similar events are occurring in individuals who have not
received the same vaccine.
The term “investigation” used here can be a simple assessment or a more rigorous
scientific evaluation of the reported AEFI in order to recognize its possible cause(s).
The extent of the investigation depends on the nature of the reported AEFI or/and
the country’s protocol to carry out the investigation. Accordingly, users of this manual
need to adapt their investigation according to the country setting and requirements
rather than strictly adhering to the manual, which describes how to carry out scientific
investigations of more serious AEFI reported by the surveillance system.
6.2 Which AEFI reports should be investigated?
Not all AEFI reports need investigation. Once the report has been received, an assessment
should be made to determine whether or not an investigation is needed.
51
September 2014
The reported AEFI must be investigated if it:
n appears to be a serious event (as defined by WHO) of known or unknown cause;

n belongs to a cluster of AEFI;
n is a previously unrecognized event associated with an old or newly introduced
vaccine;
n involves an increased number or rates of known cause;
n is a suspected immunization error;
n appears on the list of events defined for AEFI surveillance; and
n causes significant parental or public concern.
Improved reporting can lead to more AEFI reports without a real increase in true adverse
reaction rates or concerns about the vaccine product or its quality. The investigator
should determine if there is a real increase in these reaction rates, as well as identifying
the cause of the increase. For example, a change in vaccine manufacturer or in vaccine
lot can lead to a change in the reaction rate.
Criteria should be established to define the type of AEFI that requires investigation.
Protocols then need to be established at the intermediate-level and national units
responsible for AEFI surveillance to ensure that all reports requiring investigation are
adequately investigated.
6.3 Who should investigate AEFI?

The profile of investigators who carry out detailed AEFI field investigation will be
determined by the operational structure and the expertise available to the surveillance
system in the country. Many developed countries have national capacity and expertise
to conduct investigation up to the lowest level of the health system but this may not be
available to many low and middle income countries. Having a plan for responding to
serious AEFI requires each country to have identified adequate expertise tailored to its
particular cirumstances.
Sometimes the cause of the reported AEFI is very obvious, as in the case of immunization
error-related events. A basic preliminary investigation by local programme managers
may be sufficient to identify the cause.
6.4 When to investigate AEFI

The urgency of the investigation will depend on the situation. Not all AEFI require
detailed field investigation, as described above. However, if it is determined on the basis
of the preliminary information that a detailed field investigation is needed, it should
be initiated as soon as possible. It may be useful to include a “timeliness” criterion in
the evaluation of the system. For example, a criterion for initiating investigation could
be fixed as within two working days for serious events and five working days for non-
52
serious events. The criteria and timelines of an investigation (e.g. continuing problem,
high community concern) should be specified in advance.
6.5 How to investigate AEFI

An AEFI investigation follows standard principles of epidemiologic investigation (Figure
2). It is important to investigate suspected adverse events promptly and completely.
The investigator will primarily need to focus on the reported reaction as well as gather
information from the patient/parent, health workers and supervisors, and community
members. The information collected (and conclusions) should be recorded on an AEFI
investigation form. (Annex 3).
In low- and middle-income countries, immunization error-related events and coincidental

events are the commonest AEFI. Therefore, the investigator should examine the diagnosis
and background disease rates carefully and examine the evidence for any errors in the
storage, handling or administration of vaccines in considering immunization error-
related events. Attention can then focus on finding out more about the particular error
and taking the necessary corrective action. The investigator should attempt to identify
system problems rather than blaming individuals. For example, if an investigation
reveals that most abscesses are reported from one immunization clinic due to the faulty
immunization technique of a health-care worker, rather than blaming the worker, the
investigators should endeavour to find reasons why that health-care worker uses the
incorrect technique. The underlying cause could be due to a system failure such as lack
of training or lack of supportive supervision and this should be addressed.
The core variables listed by WHO for reporting (Table 9) is insufficient for the purpose of
comprehensive investigation. Countries are encouraged to use specially designed data
collection forms for the investigation. The sample AEFI investigation form (Annex 3) may
be adapted to country and situation requirements.
Investigator(s) may use WHO’s Aide-mémoire on AEFI investigation as resource material.23

This provides key definitions, guidance for preparing for an investigation, and a checklist
of useful information for each step of an investigation.
Aide-mémoire on AEFI investigation. Geneva : World Health Organization (http://www.who.int/vaccine_sa-

23
fety/publications/AEFI_Investigation_Aide_Memoire.pdf, accessed 1 August 2014).
53
September 2014
Figure 2. Steps in an AEFI investigation
Confirm information in report Collect data Collect data about vaccine and service
■ Obtain patient’s medical records About the patient: and event ■ Vaccine storage (including open vials),
■ Check details about patient and event from ■ Immunization history distribution, and disposal
medical records ■ Previous medical history, including prior ■ Diluents storage and distribution
● Verify with AEFI Report form, obtain history similar reaction or other allergies ■ Reconstitution (process and time kept)
missing details ■ Family history of similar events ■ Use and sterilization of syringes and
■ Identify other cases to be included in the ■ Clinical description, any relevant laboratory needles
investigation results about the AEFI and diagnosis event ■ Immunization of procedures (reconstitution,
■ Treatment, whether hospitalized and drawing vaccine, injection technique, safety
outcome of needles and syringes; disposal of opened
vials)
■ Do any open vials look contamined?
Conclude Investigation Test hypothesis Formulate hypothesis

■ Reach conclusion on the cause ■ Does case distribution match working ■ On the likely/possible cause(s) of the event
■ Complete AEFI Investigation Form hypothesis?
■ Take corrective action, and recommend ■ Occasionally, laboratory tests may help
further action. (see text).
It is essential to have clear working case definitions, taken from the guidelines on
reporting or defined during the investigation at the outset. Countries are encouraged
to use the Brighton Collaboration case definitions and adapt them into their own
surveillance systems. The use of common case definitions will lead to more meaningful
use of data from different countries at regional and global levels (e.g. comparison of
vaccine reaction rates). The investigation should identify all cases in the community
and find out the outcomes for all who received the suspect vaccine. The risk of disease
should be compared between those who received the vaccine and those who did not.
Proper investigation requires a working hypothesis, and this should be established as soon
as there is sufficient information. The working hypothesis may be a simple statement
linking the suspected cause with the reported AEFI. For instance, an abscess following
immunization may initially be investigated with the following hypothesis: “An abscess
following immunization due to incorrect technique”. The working hypothesis may
change during the course of the investigation. In this example, additional information
may reveal that there are similar cases from more than one clinic and therefore the
working hypothesis could be modified as “Abscess following immunization due to cold
chain failure in vaccine storage”. The focus of the investigation should be to seek to
confirm the working hypothesis.
6.6 Laboratory testing: vaccine
Laboratory testing may sometimes confirm or exclude the suspected cause. However,
testing should be requested on the basis of clear suspicion and not as a routine
procedure, and never before the working hypothesis has been formulated. Laboratory
testing is always costly. It is important to note that there is a need for a good laboratory
network (including the manufacturers) to support immunization safety surveillance.
Determination of which samples to test, if any, depends on the working hypothesis
for the cause of the event (Table 10). WHO’s guidelines on nonclinical evaluation of
54
vaccines can help.24 The vaccine may be tested for sterility, toxicity and content (e.g.
aluminium content); the diluent for sterility and chemical composition; and the needles
and syringe for sterility. It is important to monitor the cold chain of vaccine vials under
suspicion, irrespective of whether they need laboratory testing or not.
6.7 Laboratory testing: human specimens
For biochemical, histopathological and microbiological examination, specimens should

be processed at the local hospital. In case facilities are unavailable locally, specimens
should be forwarded to the most suitable laboratory in the country or even an accredited
laboratory abroad if warranted.
Table 10. Laboratory testing to investigate AEFI by working

hypothesis
Working Specimens to Laboratory test

hypothesis send
Vaccine Vaccine vial Visual test for clarity, presence of foreign matter,
transportation turbulence, discoloration or flocculation (examine
or storage under magnification)
Reconstitution Vaccine vial and/or Chemical composition analysis for abnormal

error diluents components (e.g. suspect medicine used instead
of vaccine or diluent), or microbiological culture for
bacterial contamination
Non-sterile Needle, syringe, Sterility, if an infectious cause is suspected

injection vaccine vial and
diluents
Vaccine Vaccine vial Chemical composition analysis: preservatives,

problem adjuvant level, etc. (e.g. aluminium content) or
biological tests for foreign substances or toxins if
abnormal toxicity is suspected
The date and time of collection and the type of each sample collected should be recorded
together with clinical investigations and medical records related to the incident. It is
necessary to obtain a detailed history which includes past medical history, medicine
history, immunization history, history of allergies and findings of medical records and so
on. It is advised to consult the clinician(s) treating the patient to make a decision on the
samples to be tested (see Table 11).
WHO guidelines on nonclinical evaluation of vaccines. In: WHO Expert Committee on Biological Standar-
24
dization: fifty-fourth report. Geneva: World Health Organization; 2005: Annex 1 (WHO Technical Report
Series, No 927; http://www.who.int/biologicals/publications/nonclinical_evaluation_vaccines_nov_2003.
pdf, accessed 1 August 2014).
55
September 2014
The collection and storage of specimens following serious AEFI (e.g. deaths, anaphylaxis,
toxic shock syndrome) is important. Therefore, as soon as information is received about
a suspected AEFI, the hospital staff or health-care workers (in a community setting) are
advised to collect all relevant samples such as blood, urine, cerebrospinal fluid (CSF),
vomitus, faeces, sputum, swabs etc. If there is a delay in transport to the laboratory,
samples should be stored in a refrigerator at the recommended temperature, depending
the type of sample and the facilities available.
Laboratory testing is not a routine requirement but may be a

part of an investigation.
KEY POINTS
n Laboratory testing is costly and is recommended only when it is

necessary.
n However, securing samples (vaccine vials, syringes, blood etc.) is
important because later investigation may require them.
n Therefore, proper storage and transport of suspected samples is
recommended.
Table 11. Guide to human specimen samples collection following

selected AEFI
Hypothesis Specimen Reason Specimen collection

Suspected bacterial Whole blood Bacterial culture Blood 8-10 mL in each of 2
sepsis due to blood culture bottles.
contaminated vial,
CSF Differential cell count, Sterile container
needle contamination,
biochemistry, bacterial and
coincidental Viral culture media
viral culture, PCR (HSV1/2,
enterovirus, other)
Suspected viraemia Serum IgM and IgG antibodies for Clotted blood 5-10 mls
due to vaccine virus or viral pathogens
coincidental disease
CSF Differential cell count, Sterile container
biochemistry, bacterial and
Viral culture media
viral culture, PCR (HSV1/2,
enterovirus, other)
Skin vesicle Viral culture Sterile container
Viral culture media
Suspected anaphylaxis Serum Mast cell tryptase Clotted blood 5–10 mL
Specific IgE Clotted blood 5-10 mL
Suspected toxin or drug Urine Drug screen Sterile container 1 mL

injection/ingestion, either
Blood Chemistry when indicated, liver Clotted blood or in Li
programme error or
enzymes, glucose, electrolytes Heparin 5-10 mL
coincidental
Suspected VAPP or Stool Enterovirus and viral culture Sterile container

coincidental encephalitis
56
6.8 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 administration. Apart from checking on these three factors, the
investigator 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 investigation
should promptly characterize all known cases and research similar ones (Figure 3).
Cluster identification (i.e. cases with common characteristics) is done by gathering details
(who, when and where) of vaccines administered. This can be achieved by collecting
and recording
n detailed data on each patient;

n programme-related data (storage and handling, etc.); and
n immunization practices and the relevant health workers’ practices.
Common exposures among the cases can be identified by reviewing:

n all data on vaccine(s) used (name, lot number, etc.);
n data on other people in the area (also non-exposed); and
n 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 a vaccine quality defect or an immunization
error-related AEFI. For relatively new vaccines or established vaccines used in new target
populations, a cluster may represent a previously unrecognized vaccine product-related
reaction (i.e. a signal). Awareness of vaccine reaction rates and background rates of
reported events is essential for assessing a cluster in terms of the strength of the signal
it may provide.
57
September 2014
Figure 3. Identifying the causes of an AEFI cluster
Cluster of AEFI
All cases NO NO NO Similar NO

from only one All cases got Known illness
facility? same vaccine vaccine in others who
(assume same lot or lot ? reaction? did not get
used elsewhere)
vaccine?
Immunization error,
coincidental
or unknown (Signal)
YES YES YES YES
Immunization error Coincidental event
NO
Similar Rate of NO
illness in reaction Immunization error or
Manufacturer others who did within the vaccine quality
error, batch not get the expected problem
problem or vaccine? rate?
transport/storage
error
YES YES
Coincidental event Vaccine product

reaction
If all cases received vaccines from the same health worker/facility and there are no other
cases, an immunization error is likely. If all cases received the same vaccine or lot, and
there are no similar cases in the community, a problem with the vaccine or the respective
lot is likely. If the event is a known vaccine reaction but is found to occur at an increased
rate, an immunization error or a vaccine problem are likely causes. Finally, if cases in the
unvaccinated population are occurring at about the same rate/proportion as among the
vaccinated from the same area in the same age group, the adverse event was probably
coincidental (Table 12).
Table 12. Cause-specific cluster characteristics
Cause–specific AEFI Cluster characteristics

Vaccine reaction (product- If all cases received the same vaccine or lot, and there
related or quality defect- are no similar cases in the community
related) If an increased frequency of events is reported from
multiple settings
Immunization error- related If all cases received vaccines from the same health
worker/facility and there are no other cases
Coincidental If cases include people from the same area in the same
age group who were not immunized
Immunization anxiety-related Clusters of fainting after immunization are well-

reaction recognized as anxiety-related reactions during
immunization programmes targeting adolescent girls
58
In a cluster analysis, if a previously unknown event is reported only among the vaccinated
group, it can be a potential signal provided that both immunization error-related reactions
and coincidental events are excluded. Such AEFI require comprehensive assessment and
further studies to understand their true causality (Figure 3).
6.9 Investigation of deaths
A field investigation of a death following immunization has to be conducted without

delay as the death can cause significant community concern (Table 13). All administrative
levels, including the national immunization programme, should be notified of the
death. It is recommended that death investigation should be carried out by a team
comprising clinical, laboratory and forensic experts. The team should be supported by
the programme managers. All relevant information on the event should be available to
the investigation team.
An autopsy is preferred and is recommended following all deaths suspected to be caused

by vaccine or immunization. However, the decision to conduct the autopsy should be
taken within the context of religious, cultural and the legal framework of the country.
At the time of autopsy, the autopsy surgeon should be provided documents outlining
detailed preclinical and clinical history, including laboratory and radiological findings.
Where possible, a visit to the scene of the death to gather additional evidence;
radiological examination; histopathological examination; and toxicological and
microbiological examinations will be useful. Samples for microbiology, immunology,
histopathology and virology should be collected according to the instructions given by
the relevant laboratories. Adherence to a standard autopsy protocol which allows for
a comprehensive causality assessment of a reported death following immunization is
important and necessary.
If an autopsy is not possible, a verbal autopsy can be carried out in accordance with
established guidelines and protocols. WHO protocols for verbal autopsy standards are a
useful reference.
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September 2014
Table 13. Actions to safeguard the public during an investigation
Stage of
Actions
investigation
Incident detected · n Assess and investigate with an appropriate degree of
urgency
· n Possibly quarantine suspect vaccines and take other
immediate counter actions, as appropriate
· n Begin communication with all concerned parties
Investigation starts · n Ensure that the investigator has adequate resources, and
provide more if needed
· n Increase surveillance to identify similar cases in and out
of area: sometime enhanced or active surveillance is
required to gather more information/data
· Define any suspect vaccine
· n Maintain continued communication on progress of the
investigation with all concerned parties: do not suggest
any hypothesis
Investigator develops · n Do not communicate the working hypothesis until

working hypothesis confirmed (the working hypothesis is for the investigation
team only and not for the public since, if the investigation
reveals something different from the working hypothesis,
this may affect public trust)
· n If programme-related errors are the working hypothesis,
correct them
· n If a vaccine problem is suspected, quarantine suspect
vaccines
Investigator confirms · n Advise the community of the cause and the planned
working hypothesis response
· n Communicate with all concerned parties on findings
Summary
n Investigation should be timely, comprehensive and methodical.
n Laboratory investigations are important but should not be routine. They should be conducted if
only indicated and necessary.
n It is recommended to secure investigational items (vaccine, syringes, blood etc.) in proper
condition in case if they may be needed later for laboratory investigations.
n Autopsy investigations are often essential to exclude any coincidental causes of an AEFI.
60
Bibliography:
n Surveillance for adverse events following immunization using the vaccine adverse
event reporting system (VAERS). In: Manual for the surveillance of vaccine-preventable
diseases, second edition. Atlanta (GA): Centers for Disease Control and Prevention;
2011: Chapter 21 (http://www.cdc.gov/vaccines/pubs/surv-manual/chpt21-surv-adverse-
events.html, accessed 1 August 2014).
n Verbal autopsy standards: ascertaining and attributing cause of death. Geneva:
World Health Organization; 2007 (http://www.who.int/healthinfo/statistics/
verbalautopsystandards/en/index1.html, accessed 23 August 2014).
61
7 Analysis of AEFI
incorporate inbuilt mechanisms for structured,

systematic and continued data collection.
Epidemiological analysis of data is required to
data
Immunization and vaccine safety surveillance should
measure the impact of vaccines used in the country

immunization programme and to disseminate
findings to advise programme managers, the NRA
and other stakeholders, including manufacturers.
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 rates. In considering
concerns with specific lots, it is important to have as
accurate a denominator of vaccine use as possible.
It is always the rate and not the number of reports
that should be evaluated (in comparison with known
vaccine product-related rates by lots, by different manufacturing products, and by
historical rates). For more information, refer to the Guide to the WHO information
sheets on observed rates of vaccine reactions.25
Analysis of data on AEFI should consider the following:
n reporting source (reports of AEFI by different sources may provide a wider range of
information);
n completeness of submitted AEFI forms;
n verification and reassurance of data accuracy;
n 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”;
n performance of causality assessment to classify the AEFI;
n 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);
n 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);
n comparison of these observable rates with available or expected known events,
whether vaccine reactions or background rates or historic reporting trends.
Guide to the WHO information sheets on observed rates of vaccine reactions. Geneva: World Health Organi-
25
zation (http://www.who.int/entity/vaccine_safety/initiative/tools/Guide_Vaccine_rates_information_sheet_.
pdf, accessed 1 August 2014).
63
September 2014
7.1 Who should analyse the data?
Data analysis could be carried out at different levels of the immunization safety
surveillance system: the programme implementation level, the subnational level and
the national level. The extent and purposes of analysis will vary at each level. Analysis
of data at the service provider level is very important for identifying immunization errors
and ensuring that corrective action is carried out in a timely manner. Data analysis at
higher levels with larger denominators is important to identify rare vaccine safety events
and also detect signals. The details are described in Table 14.
Table 14. Purpose of data analysis at different levels
Programme What data to analyse Purpose of data analysis at given

implementation level
level
Number of reports by These are programme operation/surveillance
clinics, hospitals, villages performance indicators (timeliness,
by a given time completeness).
Local level Reported AEFI by place Identification of immunization error-related

(immunization (clinics, hospitals), persons events will lead to corrective action.
provision level) and time
Reported AEFI by antigen Will also identify vaccine reactions and

coincidence.
Number of reports by local These are programme operation/surveillance
levels performance indicators (timeliness,
completeness) at local level.
Reported AEFI by place Identification of immunization error-related

Subnational (clinics, hospitals), persons events will lead to corrective action.
level (regional/ and time
provincial/ district/
town)
Cluster analysis Cluster analysis leads to identification
of immunization error related events,
coincidence and vaccine reactions.
Reported AEFI by antigen Will identify vaccine reactions and

coincidence.
Number of reports by These are programme operation/surveillance
intermediate levels performance indicators (timeliness,
completeness) at intermediate level.
Reported AEFI by place Cluster analysis leads to identification

(clinics, hospitals), persons of immunization error related events,
National level and time coincidence and vaccine reactions.
Cluster analysis Will identify vaccine reactions, including

detection of signals.
Reported AEFI by antigen Leads to operational and policy decisions
being taken in the country.
64
7.2 How should the data be analysed and interpreted?
Step 1: Following verification of cases, all reported AEFI data should be line-listed and/
or entered into a database. Line-listing will help initial identification of clustering or any
unusual or significant reporting events that need further analysis (Annex 4).
Step 2: AEFI data should be tabulated by place, person, time, antigens and type of event
(e.g. high fever, abscess). This step further filters the AEFI by different variables and
helps programme managers to generate clues for further analysis. Even at this step, it is
possible to identify common immunization errors. For example, an increased number of
abscesses by one immunization centre is more likely to be due to immunization-related
error. However, further investigation is necessary to confirm causality.
Step 3: AEFI rates should be calculated. The number of doses administered for each
antigen is the denominator for calculating reported AEFI rates for each antigen in a
given time period (month, quarter-year or year). Analysis should be expanded to include
AEFI rates by first, second or third dose if the antigen is administered more than once.
For this, the number of doses administered of the given antigen – by first, second or
third dose should be used as the denominator.
For instance, in a hypothetical country X, the registered child population under 1 year
of age is 5000. The coverage of measles vaccine is 90%. During the year, 20 febrile
seizures were reported following measles vaccination. The numerator for this vaccine
reaction (febrile seizures) is 20.
Selecting a proper denominator can be challenging; some options that could be

considered and their limitations are outlined in Table 15.
Table 15. 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

underestimate rate
Coverage x population May be less accurate because of variability in

coverage estimates
Target population Proxy measure for vaccine population (may also

underestimate)
In the example of country X, since no other data are available, coverage can be used to
obtain the denominator; therefore denominator = population x coverage = 5000 x 90%
= 4500. Thus the reported rate of febrile seizures is 20 (numerator)/4500 (denominator)
x 100 (multiplier) = 0.44%.
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September 2014
Use of a proper multiplier is important as it must vary by purpose and level of analysis.
At local level, percentage (%) is the best choice, whereas subnational and national
levels may use 1000, 100 000 or 1 million as the multiplier. For common, minor vaccine
reactions, percentage is recommended, and for rare serious reactions, 10 000 (104),
100 000 (105) or 1 000 000 (106) can be used (Table 3).
Step 4: Rates should be compared and interpreted. Expected vaccine reaction rates that
are available for each type of AEFI and antigen (see Annex 1 and WHO vaccine reaction
information sheets) provide a guide to decision-making on corrective action for reported
AEFI. It is also important to know the background rates of reported medical events in the
country. Background rates are independent and are not related to the vaccine. Observed
(reported) rates include both background rates and vaccine-related rates. Comparison
of background rates with reported (observed) rates of AEFI will provide support for a
conclusion on the causality of these events being due to a vaccine reaction (Table 16).
Figure 4 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 4. Vaccine reaction rate, observed rate and background

rate
Excess vaccine
reaction rates (Z)
Vaccine reactions (Y+Z)
(related to vaccine)
Known, expected vaccine Observed rate
reaction rates (Y) Background rates
(detected in pre & post
licensure studies,
surveillance)
Observed rates (X+Y+Z) Background rates (X)

Total number of cases reported (not related to vaccine)
from both vaccinated and un
vaccinated groups Occur among un vaccinated,
recorded prior to or
simultaneously to
vaccination
*Rates can be expressed per 1000, 10000 or 100,000
Note: Vaccine reaction rate = observed (reported) rates – background rates (not related to vaccine).
66
Vaccine reaction rates are further divided into two subcategories: expected vaccine
reaction rates and excess vaccine reaction rates. The WHO vaccine reaction information
sheets26 give the “expected” vaccine reaction rates (the “Y” component in Figure 4),
which are based on pre-licensure and post-licensure data. These expected vaccine
reaction rates are known rates due to the inherent properties of the vaccines and the
response by recipients. If the value exceeds the “expected” vaccine reaction rates, one
should consider whether this is a true increase in the vaccine reaction rate or if the
values are due to other factors.
In addition, these reported vaccine reaction rates depend on the reporting source – such
as type of surveillance (active, passive, enhanced passive), special studies etc. Further,
these reports may also differ, as outlined in the manufacturer’s package information,
and therefore the rates should be interpreted with caution.
Table 16. Factors to consider when comparing rates of AEFI

Vaccines
Although a vaccine may have the same antigens as another, different manufacturers may produce
vaccines (or lots of the same vaccine) that differ substantially in their composition, including the
presence (or not) 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 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. For example, the DTaP vaccine given as a primary dose is less likely to result in
extensive limb swelling when compared with the same vaccine given as a booster dose.
Case definition
Adverse events may be defined differently in surveillance/research studies that do not use the same
case definition. Not using standardized case definitions may consequently affect the estimation of the
AEFI rate. The Brighton Collaboration has developed case definitions for many vaccine reactions (www.
brightoncollaboration.org).
Time period
It is important that estimates of AEFI rates are limited to a given time period (e.g. quarterly, annually)
to enable a valid comparison to be made. This is helpful when interpreting AEFI rates due to possible
vaccine reactions or coincidental events. It also adds to the validity of the rates as the denominator
(vaccine doses administered in a given time period) contributes to more accurate estimates.
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-licensure 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 instance, reports of
death post-vaccination may be higher in a country that has a higher background rate of deaths due to
coincidental infections.
WHO vaccine reaction rates information sheets. Geneva: World Health Organization (www.who.int/vac-
26
cine_safety/initiative/tools/vaccinfosheets, accessed 1 August 2014).

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September 2014
In the scenario presented here, we can compare the observed rate of 0.44% febrile
seizures reported in country A with the expected rate of febrile seizures following
measles-containing vaccines, which is 0.03%. Thus the observed (reported) rate of
0.44% is greater than the expected vaccine reaction rate of 0.03% and therefore
warrants investigation. We ask ourselves whether the case definition is correct, whether
the onset interval concurs with the interval of the reported febrile seizures cases after
vaccination or if something is wrong with the vaccine product. In any analysis of vaccine
adverse events, confounders or sources of bias that should be considered include (but
are not limited to) age, gender, race/ethnicity, season (e.g. for influenza vaccines) and
country/region.
At the international level, data analysis aims mainly to identify the signals and compare
pre-licensure and post-licensure safety data, and to share the findings with countries
to support the decision-making. The data analysis also helps manufacturers to ensure
vaccine safety during production of vaccines.
7.3 How should a cause be determined?
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 in one of the
categories of AEFI. For a few medical events, the diagnosis itself will show whether
the cause is immunization error-related, vaccine-related, coincidental or an injection
reaction. In other cases, additional information and evidence may be required to identify
the cause.
Comparing background data with reported (observed) data does not conclude the
search for 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 non-vaccinated persons, 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 the design of
epidemiological studies (case series, case-control cohort studies) will strengthen the
conclusion of causality.
68
Summary
Data analysis is important for identifying problems, generating a hypothesis and then
testing the hypothesis.
n Data need to be cautiously interpreted: compare rates but not absolute numbers, give attention
to case definitions and use accurate denominator data, if available. WHO information sheets on
vaccine reaction rates provide rates of reactions to specific vaccines that can be helpful when
comparing rates. Reported vaccine reaction rates depend on the reporting source such as type
of surveillance and special studies, and therefore these rates must be interpreted with caution.
n Comparing background data with observed data does not prove causality. It only generates the
hypothesis. To conclude that a vaccine causes a vaccine reaction, it is necessary to demonstrate
that the risk in vaccinated individuals is greater than that in non-vaccinated persons.
n Analysis and interpretation of reporting rates will begin to identify vaccine and vaccination
problems. Therefore it is important to have a comprehensive reporting system with a high
reporting coverage. For this purpose, a search for additional cases, particularly during
investigations, is necessary since underreporting is common in passive/spontaneous
surveillance systems.
Bibliography:
n Bonhoeffer J, Bentsi-Enchill A, Chen RT, Fisher MC, Gold MS, Hartman K et al.
Guidelines for collection, analysis and presentation of vaccine safety data in pre- and
post-licensure clinical studies. Vaccine. 2009;27:2282–88.
n LeBaron CW, Daoling Bi, Sullivan BJ, Beck C, Gargiullo P. Evaluation of potentially
common adverse events associated with the first and second doses of measles-
mumps-rubella vaccine. Pediatrics. 2006;118:1422–30.
n WHO vaccine reaction rates information sheets. Geneva: World Health Organization;
2012
– List of information sheets with links: www.who.int/vaccine_safety/initiative/tools/
vaccinfosheets, accessed 1 August 2014.
– Guide to the WHO information sheets on observed rates of vaccine reactions:
http://www.who.int/entity/vaccine_safety/initiative/tools/Guide_Vaccine_rates_
information_sheet_.pdf, accessed 1 August 2014.
69
8 Causality assessment
of an AEFI
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 (Table 17). 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 vaccinee 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.
A companion document to accompany this chapter is the WHO publication Causality

assessment of an adverse event following immunization (AEFI) – User manual for the
revised WHO classification (see Bibliography). It should be acquired to complement this
material.
Table 17. Usefulness and limitations of standardized case

causality assessment
What causality assessment can do What causality assessment cannot do

Classify the likelihood of a relationship Change uncertainty to certainty
Prove the connection between vaccine and
event
Decrease disagreement between case Give accurate/quantitative measurement of the
assessors likelihood of a relationship
Improve scientific evaluation of cases; Quantify the contribution of a vaccine to the
education development of the adverse event
Distinguish classifiable from unclassifiable
Mark individual case reports
cases
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September 2014
Causality assessment is important for:
n identification of vaccine-related problems;

n identification of immunization error-related problems;
n excluding coincidental events;
n detection of signals for potential follow-up, testing of hypothesis and research; and
n validation of pre-licensure safety data with comparison of post-marketing surveillance
safety data.
The quality of the causality assessment depends on three factors:
1. the performance of the AEFI reporting system in terms of responsiveness and

effectiveness (the quality of case reporting and follow-up investigation);
2. 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
3. the quality of the causality review process, including access to appropriate
expertise.
With inadequate or incomplete case information, an adequate causality assessment

cannot be performed or, if attempted, the AEFI may be deemed unclassifiable or
not assessable due to lack of information. On the other hand, even with complete
information the AEFI may be categorized indeterminate due to the lack of clear evidence
of a causal link, or conflicting external evidence or other inconsistencies. Nevertheless,
these assessments should be recorded because the reporting of more cases may lead to
a stronger signal and a plausible hypothesis, or stronger refutation of any link.
In summary, causality assessment usually will not prove or disprove an association

between an adverse event and the immunization. It is meant to assist in determining
the level of certainty of such an association. A definite causal association or absence of
association often cannot be established for an individual event.
8.1 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. The details are outlined in the Table
18.
72
Table 18. Assessing causality at different levels
Population level: Surveillance data and an appropriate statistical methodology are used
to test the hypothesis that there is a causal association between the use of a vaccine
and a particular AEFI. At the population level the aim is to answer the question “Can
the given vaccine cause a particular adverse event?” This may sometimes be combined
with causality assessment at the individual level (of AEFI 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.
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.
Investigation of signals: The assessment of whether a particular vaccine is likely to cause

a particular AEFI takes into account all evidence: individual AEFI cases, surveillance data
and, where applicable, cluster investigations as well as nonclinical data.
8.2 Scientific basis : 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.
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September 2014
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).
8.3 Case selection for AEFI causality assessment
Not all AEFI incidents that are reported, even if investigated in detail, need to be subject
to a formal causality assessment. In some cases, it becomes immediately clear that
symptoms began before the vaccination. It is generally recommended that causality
assessment should be done for the following:
n serious AEFI, according to the regulatory definition of serious (i.e. events which
are life-threatening or leading to death, hospitalization, significant disability or
congenital anomaly), where it is important to evaluate whether a vaccine could
have been responsible for the event;
n clusters of events above an expected rate or level of severity, where it is important
to establish whether the number of cases related to vaccination is truly elevated and
thus action needs to be taken; and
n signals generated as a result of an unusual individual case or a cluster of cases that
then will warrant further analysis or investigation.
Other AEFI may also be subject to a causality assessment if there is a need to assess
them in more detail given their potential need for a detailed investigation or follow-up,
as outlined below:
n AEFI that may have been caused by immunization error (e.g. bacterial abscess, severe
local reaction, high fever or sepsis, BCG lymphadenitis, toxic shock syndrome);
n significant events of unexplained cause occurring within 30 days after a vaccination
(and not listed in the product label); and
n events that are causing significant parental or community concern and where a
formal case assessment can provide a detailed, more reassuring explanation to the
parents and/or community (e.g. HHE, febrile seizures).
8.4 Steps to be taken before starting a causality assessment
There are three prerequisites before a causality assessment is conducted, namely:
1. The AEFI case investigation should have been completed. Premature assessments
with incomplete investigation could mislead the classification of the event. When an
investigation is incomplete, follow-up efforts to obtain additional information and
documents should be made.
74
2. 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.
3. There must be a “diagnosis” (see below) using standard or widely accepted criteria
for the adverse event, clinical sign, abnormal laboratory finding, symptom and/or
disease in question. In other words, it should be clearly understood which vaccine is
being associated with what specific event that was reported.
8.5 Causality assessment method
The WHO publication Causality assessment of an adverse event following immunization

(AEFI) – User manual for the revised WHO classification was developed by WHO as a
method for assisting national committees for AEFI case review and causality assessment.
It was patterned on an algorithm developed in the USA by the Clinical Immunization
Safety Assessment network and with new AEFI definitions proposed by the Council for
International Organizations of Medical Sciences (CIOMS).
The revised WHO causality algorithm focuses on two critical questions: “Is there evidence
in literature that this vaccine(s) may cause the reported event even if administered
correctly?” and “Did the event occur within an appropriate time window after vaccine
administration?” WHO’s Aide-mémoire on causality assessment outlines the algorithm
and summarizes the process and should be kept handy.27
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 I).
Step 3. Algorithm: to obtain direction as to the causality with the information gathered
in the checklist.
Step 4. Classification: to categorize the AEFI’s association to the vaccine/vaccination

on the basis of the direction determined in the algorithm.
Step 1: Eligibility
It may be self-evident, but to proceed with causality assessment it is necessary first to
confirm that the vaccine was administered before the event occurred (Figure 5). This can
be ascertained by eliciting a careful history from the relevant stakeholders to ascertain
the timing of vaccination and of the onset of any signs and/or symptoms related to the
27
WHO Aide-mémoire on causality assessment. Geneva, World Health Organization (http://www.who.int/vac-
cine_safety/publications/AEFI_aide_memoire.pdf, accessed 1 August 2014).
75
September 2014
event being assessed. It is also essential to be clear on the “diagnosis” of the reported
AEFI. The valid diagnosis could be a clinical sign, symptom, abnormal laboratory finding
or disease with clear details regarding onset. The diagnosis should also meet a standard
case definition for the disease process that is being assessed. If available, it is best to
adopt one of the Brighton Collaboration case definitions (see Bibliography). However,
if this is not possible, case definitions can be adapted from the published medical
literature, national guidelines or local clinical practice. If the reported event does not
have a valid diagnosis, it may not be possible to categorize the AEFI adequately and
additional information should be collected in order 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
that takes each vaccine into account separately.
Figure 5. Causality assessment: eligibility

Source: Causality assessment of adverse event following immunization (AEFI): user manual for the revised WHO classification. Geneva: World Health
Organization; 2013.
AEFI  Ensure AEFI investigation is completed and all details of the case are available
case  Retain case details in a retrievable database for «data mining»
Identify  Identify one or more vaccines administered before this event

vaccine(s)
Valid  Select the unfavourable or unintended sign, abnormal laboratory finding,

Diagnosis symptom or disease that is thought to be causally linked to the vaccine
Use an appropriate definition (Brighton Collaboration definition, standard

Case

literature definition, national definition or other approved definition) to assess

definition diagnostic certainty
If an AEFI is reported and appears to not meet the eligibility criteria because of
suspected inadequate information, it is important to make attempts to collect the
additional information required in order to ensure that the case can be properly assessed
76
for eligibility. Additionally, all cases reported (including those deemed, or eventually
deemed, ineligible) 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 reviewers should define the “causality
question” (Figure 6).
Figure 6. Causality question
Create your question on causality here:
Has the vaccine/vaccination caused ?
(The event for review in step 2)
Organization; 2013.
Step 2: Checklist
The checklist contains elements to guide the assessor or committee of reviewers to
collate the evidence for case review (Table 19). It is designed to assemble information
on patient-immunization-AEFI relationships in the following key areas:
1. Is there evidence for other causes?

2. 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
3. Is there any strong evidence against a causal association?
4. Other qualifying factors for classification (e.g. background rate of the event, present
and past health condition, potential risk factors, medication, biological plausibility,
etc).
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September 2014
Table 19. The causality assessment checklist
I. Is there strong evidence for other cause?

n Does a clinical examination, or laboratory tests on the patient, confirm another
cause?
II. Is there a known causal association with the vaccine or vaccination?

Vaccine product(s)
n Is there evidence in the literature that this vaccine(s) may cause the reported event
even if administered correctly?
n Did a specific test demonstrate the causal role of the vaccine or any of the
ingredients?
Immunization error
n Was there an error prescribing or non-adherence to recommendations for use of
the vaccine?
n Was the vaccine (or any of its ingredients) administered unsterile?
n Was the vaccine’s physical condition abnormal at the time of administration?
n Was there an error in vaccine constitution/preparation by the vaccinator?
n Was there an error in vaccine handling?
n Was the vaccine administered incorrectly?
Immunization anxiety
n Could the event have been caused by anxiety about the immunization?
II. (time). If “yes” to any question in II:

n Was the event within the time window of increased risk, after vaccine administration?
III. Is there strong evidence against a causal association?

n Is there strong evidence against a causal association?
IV. Other qualifying factors for classification

n Could the event occur independently of vaccination (background rate)?
n Could the event be a manifestation of another health condition?
n Did a comparable event occur after a previous dosc of a similar vaccine?
n Was the exposure to a potential risk factor or toxin prior to the event?
n Was there the acute illness prior to the event?
n Did the event occur in the past independently of vaccination?
n Was the patient taking any medication prior to vaccination?
n Is there a biological plausibility that the vaccine could cause the event?
Organization; 2013.
(See Annex 5 for the standard template of the checklist.)
78
Step 3: Algorithm
The algorithm (Figure 7) follows the key questions and related answers on the
checklist. A stepwise approach using the algorithm helps determine if the AEFI could
be consistent, or inconsistent, with an association to immunization, or is indeterminate
or unclassifiable.
A detailed description of the algorithm and how to make use of it is in the user manual
from which it is taken. In particular, some of the responses – such as those to IA, IIA
and IIIA – have greater strength and these conclusions have greater weight. When
the conclusion is “unclassifiable”, the reviewers should determine the reasons why
classification was not possible and all attempts should be made to obtain the necessary
missing information or evidence to allow for a classification.
Figure 7. Causality assessment: algorithm
I A. Inconsistent III A. Inconsistent

causal causal
association association
to immunization to immunization
YES
YES
II. Is there a III. Is there a IV. Review

I. Is there strong known causal other
evidence for strong evidence
association with against a causal qualifying
other causes? the vaccine/ factors
association?
vaccination
YES
NON
IV D.
Is the event Unclassiable
II (Time). Was the classiable?
event within the
time window of
increased risk? YES
YES
II A. Consistent IV A. Consistent IV B. IV C. Inconsistent

causal causal Indeterminate causal
association association association
to immunization to immunization to immunization
Organization; 2013.
Step 4: Classification
The final classification is based on there being available adequate information for the
case, as mentioned above. After working through the algorithm, a case can be classified
as follows (Figure 8):
Consistent causal association to immunization

A1: vaccine product-related reaction, or
A2: vaccine quality defect-related reaction, or
A3: immunization error-related reaction, or
A4: immunization anxiety-related reaction.
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September 2014
Indeterminate
B1. The temporal relationship is consistent but there is insufficient definitive evidence for
the vaccine causing the event. It may be a new vaccine-linked event. This is a potential
signal and needs to be considered for further investigation.
B2. Reviewing factors result in conflicting trends of consistency and inconsistency with
a causal association to immunization.
Inconsistent causal association to immunization (coincidental)
This could be due to underlying or emerging condition(s), or conditions caused by

exposure to something other than the vaccine. A case without adequate information
for a conclusion on causality is “unclassifiable” and requires additional information
for further review. The available information on unclassifiable cases should be placed
in a repository or electronic database which should be reviewed periodically to see
if additional information is available for classification and to perform analyses for
identifying signals.
Figure 8. Causality assessment: classification
A. Consistent causal B. Indeterminate C. Inconsistent causal

association to immunization association to immunization
A1. Vaccine product-related B1. *Temporary relationship is

reaction (As per published literature) consistent but there is insufficient
definitive evidence for vaccine causing C. Coincidental
Adequate event (may be new vaccine-
information A2. Vaccine quality defect- linked event) Underlying or emerging condition(s),
related reaction
available or condition(s) caused by
exposure to something other
B2. Qualifying factors result in than vaccine
A3. Imminization error-related
reaction conflicting trends of consistency and
inconstistency with causal association
to immunization
A4. Immunization anxiety-
related reaction
Unclassifiable
Adequate
information Specify the additional information required for classification
not available
*B1: Potential signal and*B1: Potential

maybe consideredsignal and maybe
for investigation considered for investigation
Organization; 2013.
Countries are encouraged to adopt the new revised causality assessment process during
the expert committee reviews. The final classification (Step 4) is critical as it provides
direction to follow-up actions. It is important to note that the final classification of a
given AEFI may change as knowledge and information are updated.
When AEFI occur as clusters, it is important to consider each case separately and do
an independent causality assessment and classification for each case in the cluster.
After classification, the cases should be line-listed to see if a pattern emerges. Pattern
identification is important for guiding action to be taken as well as for identifying signals.
80
8.6 Action to be taken after causality assessment
Regardless of the outcome of causality assessment, the lessons learned should provide
insights on the immunization programme for the technical, immunization programme
and administrative managers. Findings should be promptly and clearly communicated
and the messages on any next steps to be taken should also be clear. These should include
communicating reassurance or the need to take specific actions in the programme –
including training, research, modifying systems, refining tools and so on – to avoid and/
or minimize recurrences.
National immunization programmes need to establish standard protocols for responding

to AEFI. These have to be decided by a national committee and approved by the existing
decision-making system in the country. The following section provides some examples of
the types of responses that can be taken to the different causality conclusions resulting
from the assessment.
A. Consistent causal association to immunization
A1. Vaccine product-related reaction
It will be necessary to follow protocols adopted by each country when such cases are
confirmed.
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 NRA and the marketing
authorization holder about the AEFI. The event should be communicated to the
manufacturer through these bodies.
WHO should be contacted through the Organization’s local country office or the
WHO Uppsala Monitoring Centre (http://www.who-umc.org/) and the information
communicated to ensure that other countries using the vaccine are alerted.
A3. Immunization error-related reaction
Training and capacity-building are critical to avoid recurrences of such reactions.
A4. Immunization anxiety-related reaction
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. Later this
may 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.
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September 2014
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 case can be reclassified to a more definitive category. During the
assessment, the 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)28 can be approached for guidance through WHO, particularly when an event
is likely to affect the immunization programme significantly.
C. Inconsistent causal association to immunization (coincidental)

The information and confirmation should be provided to patients, their relatives, the
care provider and the community.
Summary
n Causality assessment is the systematic review of individual or population data about an AEFI
case to determine the likelihood of a causal association between the event and the vaccine(s)
received.
n The quality of the causality assessment depends on factors such as the effectiveness of the
reporting system and the quality of the causality review process.
n Regardless of whether an AEFI is attributable to the vaccine or the vaccination programme,
causality assessment determines what steps need to be taken to address the event.
For the Global Advisory Committee on Vaccine Safety (GACVS), see: http://www.who.int/vaccine_safety/
28
committee/en/.
82
Bibliography:
n Adverse effects of vaccines: evidence and causality. Washington (DC): Institute of
Medicine; 2100 (www.iom.edu/Reports/2011/Adverse-Effects-of-Vaccines-Evidence-
and-Causality.aspx, accessed 1 August 2014).
n Halsey NA, Edwards KM, Dekker CL, Klein NP, Baxter R, Larussa P et al. Algorithm
to assess causality after individual adverse events following immunizations.
Vaccine. 2012;30(39):5791-8. Epub 2012 Apr 14.
n Hill AB. The environment and disease: association or causation? Proc R Soc Med.
1965;58:295–300.
n Kohl KS, Gidudu J, Bonhoeffer J, Braun MM, Buettcher M, Chen RT et al. The
development of standardized case definitions and guidelines for adverse events
following immunization. Vaccine. 2007;25:5671–4. Epub 2007 Mar 12.
n Standard case definitions by the Brighton Collaboration (https://brightoncollaboration.
org/public/what-we-do/setting-standards/case-definitions.html, accessed 23 August
2014).
n Stratton KR, Howe CJ, Johnston RB, editors. Adverse events associated with childhood
vaccines: evidence bearing on causality. Washington (DC): Institute of Medicine,
National Academy Press; 1994.
n Causality assessment of an adverse event following immunization (AEFI) – user manual
for the revised WHO AEFI causality assessment classification. Geneva: World Health
Organization; 2013 (http://www.who.int/vaccine_safety/publications/aevi_manual.pdf,
n Causality assessment of adverse events following immunization. Wkly Epidemiol Rec.
2001;76:85–92.
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9 Actions and
to AEFI
follow-up
Responding to AEFI may involve 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.
9.1 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 workers 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 (as recommended in the country guidelines).
9.1.1 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 considered to be
very rare and the risk (in general) is 1-2 cases per million vaccine doses.
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 is the reaction. Symptoms limited to only one system can occur,
leading to delay in diagnosis. Biphasic reactions where symptoms recur 8-12 hours after
onset of the original attack, and prolonged attacks lasting up to 48 hours, have been
described.
Events happen without warning. Emergency equipment must be immediately at hand

whenever immunizations are given. All vaccinators must be familiar with the practical
85
September 2014
steps necessary to save life following anaphylaxis.29 Each vaccinating centre must have
an emergency kit with adrenaline. 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. It is important to note that health-care workers may misdiagnose syncope
attack as anaphylaxis and administer adrenaline as a part of the emergency care. If
the correct dose of adrenaline according to age and weight is administered via the
intramuscular route, no harm is likely to occur. However, an overdose, by administering
intravenous or intra-cardiac adrenaline or by repeated administration, may cause harm.
Table 20. Conditions that may be mistaken for anaphylaxis post-

immunization
Diagnosis Onset: symptoms and signs

Vasovagal event Symptoms are usually immediate (< 5minutes) and
commence during the injection process. No skin
rash, bradycardia not tachycardia, no respiratory
involvement, spontaneous resolution when prone.
Hypotonic hyporesponsive Onset 2-6 hours post-immunization, sudden pallor,
episode hypotonia and unresponsiveness, usually in an
infant. No skin rash, 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 apnea or aspiration.
Aspiration of oral vaccine (e.g. Immediate respiratory symptoms (cough, gagging,
OPV or rotaviral vaccine) stridor or wheeze) during administration, usually in
infant. No skin rash or cardiovascular compromise.
Somatic conversion Immediate or delayed respiratory symptoms, syncope,
symptoms 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
cause.
Immunization-error related Immediate toxic drug reaction with symptoms and
signs due to drug toxicity. Reported with immunization-
error related which have resulted from inadvertent
administration of a muscle relaxant or insulin.
29.
Protocol for management of suspected anaphylactic shock. Winnipeg, Government of Manitoba; 2007
(http://www.gov.mb.ca/health/publichealth/cdc/protocol/anaphylactic.pdf, accessed 1 August 2014).
86
For all cases of suspected anaphylaxis it is important all symptoms and signs are well
documented by health-care providers (e.g. immunization providers, ambulance records,
Emergency Department clinical notes). The Brighton Collaboration case definition
for anaphylaxis should be consulted for a list of possible symptoms and signs of the
condition, and subsequent review can ascertain if the case definition of anaphylaxis is
met. Elevated mast cell tryptase is included in the case definition and potentially this
could be helpful, but it is rarely considered in a primary care or emergency department
setting where children are likely to present post-immunization.
Because anaphylaxis is very rare, other causes of sudden and severe symptoms post-
immunization that occur more commonly than anaphylaxis need to be considered. Table
20 lists those conditions which may be mistaken for anaphylaxis.
9.2 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 programme 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 21). However, it must be accepted that in some cases the
relationship to vaccine will never be clear.
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September 2014
Table 21. 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
reaction or lot, obtain information from the manufacturer and consult with
the WHO regional office 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 workers;
§ 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.
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- error related 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 programme 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. Communication is dealt with in Chapter 10.
9.2.1 Logistics
The immunization supply chain, injection safety and waste management are all part
of immunization safety surveillance. Countries are encouraged to improve their supply
chain system and ensure safe injection practices.
With regard to vaccine-related reactions, decisions should be carefully thought out. The
reliability of the evidence on which the decision is based, the impact on the immunization
programme and availability of alternate sources of vaccine all need careful scrutiny.
Communication with the vaccine manufacturer and WHO is advisable before any hasty
decision is made.
Investigation of AEFI offers an opportunity for training and enhancing awareness

among staff. Irrespective of the type or outcome of the AEFI, it can be used to update
88
knowledge and develop skills and confidence among the staff. Further, awareness can
expand to involving all stakeholders linked to the immunization programme – including
academia, teachers, volunteers, NGOs, policy-makers, politicians and the media.
Immunization safety surveillance should include training that will enable appropriate
responses at all levels of the system. It is also important to learn more about the process
and outcomes in immunization safety from past experience.
9.3 Training and training opportunities for vaccine safety
WHO has developed a training programme targeting immunization service providers

at different levels. The training modules are routinely updated and guidelines for both
facilitators and trainees are available in printed and electronic forms. WHO is supporting
countries to conduct both basic training and advanced causality assessment training
programmes.
To strengthen vaccine safety capacity among staff in countries, WHO has developed
an online platform that offers training to national public health officials, immunization
programme managers, vaccination staff and members of AEFI review committees.30 In
2012 an e-learning course was developed by WHO for those engaged in immunization
safety surveillance activities.31
9.3.1 E-learning course on vaccine safety basics
The e-learning course on vaccine safety basics, developed by WHO in collaboration

with international vaccine safety experts, is a flagship course aiming to establish shared
understanding among all staff and officials working on vaccine safety-related issues.
Programme managers and all who are actively involved in and responsible for
immunization services are encouraged to use the free online course. As the training
course is self-guided and user-friendly, it can be taken in any setting and over any period
of time. The e-learning course material is available at the link indicated. The course
comprises six modules, through which the learner can acquire detailed information on
immunological aspects of vaccine safety, characteristics of AEFI, vaccine pharmacovigilance
components, surveillance systems, national and international vaccine safety institutions
and their services. The course also includes a module on communication, including risk
communication to vaccinees, their parents and communities, as well as advice on how
to communicate effectively with the media. Modules include case studies, summaries
and assessments.
Technical support and trainings. WHO Global Vaccine Safety Resource Centre. Geneva: World Health Organiza-
30
tion (http://www.who.int/entity/vaccine_safety/initiative/tech_support/en/index.html, accessed 1 August 2014).

The WHO e-learning course on vaccine safety basics. Geneva: World Health Organization (http://www.vaccine-
31
safety-training.org, accessed 1 August 2014).
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September 2014
9.3.2 Vaccine safety basic training
This basic course is designed for three days training. It consist of six modules covering
the following areas: introduction to vaccine safety, types of vaccines and other
components, AEFI and data analysis, AEFI surveillance (reporting, investigation and
causality assessment), vaccine safety institutions and mechanisms, and communication.
In addition, the course includes group work and evaluations of each module and of
the overall course. The manual for facilitators and the workbook for participants are
available.
The following are likely to benefit from this training:
n persons in the NRA dealing with clinical evaluation of biological products and
vaccines;
n persons in the NRA responsible for pharmacovigilance (preferably those specifically
involved in vaccine safety);
n the national immunization programme manager and Ministry of Health staff
responsible for post-marketing surveillance of vaccines, particularly relating to AEFI;
n persons in the national immunization programme responsible for the management
of disease surveillance;
n physicians with experience in the field of pharmacovigilance and/or immunization
and who are concerned with vaccine and medicines policy;
n persons in the Ministry of Health responsible for press releases/media reports or
reactions to reports in the media;
n persons in the Ministry of Health responsible for public education, social mobilization
and support for vaccination, especially with respect to the national immunization
programme;
n representatives of agencies who will support regional and national activities in
vaccine safety.
9.3.3 Vaccine safety advance training
This advanced course is designed for five days training. It consists of 10 modules covering
the following areas: course introduction, AEFI basic concepts, methods for monitoring
and conducting surveillance of AEFI, investigation of AEFI, analysis of vaccine safety
data, AEFI causality assessment with case definitions and case studies, global initiatives
to support monitoring and causality assessment, causality assessment follow-up, and
vaccine risk communication. In addition, the course includes group work and evaluations
of each module and the overall course. The manual for facilitators and workbook for
participants are available.
90
Summary
n Treating the patient is the first priority following an AEFI. Preparedness for managing serious
adverse events is important and necessary. Each vaccination centre should have minimum
facilities (emergency tray and trained personal) for managing anaphylaxis.
n Anaphylaxis is extremely rare. Syncope attacks are common and are often misdiagnosed as
anaphylaxis. Administering a single and correct dose of adrenaline by the intramuscular route,
even to a patient with syncope but misdiagnosed as anaphylaxis, does not cause harm.
n The response and follow-up to the AEFI will depend on the findings of the investigation.
n It is worth disseminating the results of the investigation so that others can learn from
the experience. The investigation can also serve as a useful teaching resource in training
investigators in the future.
n Immunization errors will need to be corrected. There should be a checking mechanism to ensure
that they do not reappear.
n For coincidental events, the main task is communication to maintain confidence in the
immunization programme.
n Training is an important component of the vaccine safety surveillance system and its follow-
up activity. Programme managers should use training as an opportunity to strengthen
immunization programme in the country.
Bibliography:
n Emergency treatment of anaphylactic reactions. London: Resuscitation Council; 2008.
n Global learning opportunities for vaccine quality. Geneva: World Health Organization
(www.who.int/immunization_standards/vaccine_quality/gtn_index, accessed 1 August
2014).
n Good information practices for vaccine safety web sites. Geneva: World Health
Organization (http://www.who.int/vaccine_safety/initiative/communication/network/
vaccine_safety_websites/en/, accessed 1 August 2014).
n Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM. The diagnosis and
management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol.
2010;126(3):477–80.
n Nokleby H. Vaccination and anaphylaxis. Current Allergy Asthma Reports. 2006;6:9–13.
n WHO/EPI manual Training for mid-level managers. Making disease surveillance work.
Geneva: World Health Organization; 2008 (WHO/IVB/08.08; http://whqlibdoc.who.int/
hq/2008/WHO_IVB_08.08_eng.pdf, accessed 1 August 2014).
n WHO Global Vaccine Safety Resource Centre (GVS RC). Geneva: World Health
Organization (http://www.who.int/entity/vaccine_safety/initiative/tech_support/en/
91
10 index.html, accessed 1 August 2014).
Communication
Although managing a country’s immunization

programme requires in-depth knowledge of the
technical aspects of vaccination, programme
managers are also increasingly being asked to respond
to communications issues caused by real or perceived
AEFI. Communication with parents, the community,
health staff 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.
Trust is a key component in the exchange of information at every level. Any overconfidence
about risk estimates that are later shown to be incorrect contributes to a breakdown
of trust among the people involved. Uncertainty about AEFI should be acknowledged,
there should be a full investigation, and the community should be kept informed.
Premature statements about the cause of the event before the investigation is complete
should be avoided. If the cause is identified as immunization-related error, it is vital not
to lay personal blame on anyone, but to focus on system-related problems that resulted
in the error(s) and the steps being taken to correct them.
In communicating with the community, it is useful to develop links with community

leaders and local health workers so that information can be rapidly disseminated.
Maintaining lines of communication with the community is important throughout the
investigation. Upon completion of the investigation, the cause of the event(s) must be
communicated to the community. This communication must include information about
the steps being taken to remedy the situation and to prevent a recurrence, if such steps
are needed.
None of the advice or steps contained in this manual should be construed as suggesting
that communicating vaccine safety is easy. In this age of instant communication, as
outlined in a manual of WHO’s Regional Office for Europe, “the ease with which
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September 2014
information can be disseminated now means that negative comments about vaccines
can go ‘viral’ on the Internet without balanced professional input. As a result, the media
have found rich pickings in vaccine safety issues”.32 Employing strong communication
principles and strategies is not a substitute for evidence-based risk analysis, but having a
communications plan for rapid implementation may prevent vaccine safety scares from
become crises.
10.1 Communication with stakeholders
There are many parties to whom communications should be tailored in order to meet
their particular needs. These include:
n parents and the community;

n health staff;
n particular stakeholders such as the Ministry of Health, NRA, NCL, politicians,
professionals, academia, international agencies, WHO, UNICEF, and manufacturers;
n the media.
In addition, there are principles of communication that apply to most if not all audiences.
These include the need to:
n listen empathetically to concerns;

n reassure and support but do not make false promises;
n communicate frequently;
n build up and maintain relationship among the stakeholders;
n inform audiences about possible common adverse events and how to handle them;
n prepare fact sheets on adverse events and other key information for all audiences;
n 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 not on the health worker(s), but
focus on the correction and quality of the national immunization system.
While health staff, because of the nature of their work, should have some training, or
at least experience in communication skills, communication with staff by public health
authorities and investigators should be sensitive to their needs. Therefore:
n Communication should include all levels of health authorities involved.

n Reassure the staff of their knowledge, ability, skills and performance.
n Do not blame health worker(s) but focus on the correction and quality of the national
immunization programmme.
Vaccine safety events: managing the communications response. A guide for Ministry of Health EPI ma-
32
nagers and health promotion units. Copenhagen: World Health Organization Regional Office for Europe;
2013 (http://www.euro.who.int/en/health-topics/disease-prevention/vaccines-and-immunization/publica-
tions/2013/vaccine-safety-events-managing-the-communications-response).
94
n Keep health workers updated on the investigation process, progress, and findings.
Vaccine safety information needs to be shared with other stakeholders in order

to ensure the dissemination of correct information and, by doing so, to ensure the
smooth functioning of the national immunization programmme. This may be
done in two stages: sharing preliminary information at the initial stage and sharing
the final data/report after completion of the investigation/causality assessment.
10.2 Communicating with the media
The media (newspapers, radio, television and the Internet) play an important role
in public perception. Understanding what the media want from a story will assist
communication with them. In certain situations, media coverage can lead to public
concern about immunization. In these situations, it is important to coordinate with
professional organizations, health professionals and health-care workers before
responding to or addressing the media. The coordination should include preparation on
dealing with public concern about this issue in order to minimize any potential harm to
the immunization programme. It is also useful to have other groups and individuals that
merit public respect and authority to publicly endorse and strengthen key immunization
messages.
Communicating with the media requires particular skills that call for training. Reporters
are highly trained professionals and are and their perspective must be properly
understood. The media are interested in stories that will attract attention. While the
success of a vaccination programme can attract attention, so can a programme that
has not gone as planned. Dramatizing and personalizing events can both highlight
success as well as create a sense of panic about an AEFI with a particular vaccine
product – regardless of whether the AEFI is unrelated to immunization (coincidental)
or is a localized immunization error. One other important fact is the media want early
responses to their questions: therefore waiting for the conclusion of an investigation is
rarely possible. Information may need to be disseminated early and often, and it is vital
to be honest about what is known and what is not known, and to avoid being evasive
and unresponsive.
At the same time, the media can be leveraged positively for the benefit of immunization.
Health topics are popular among the public and, therefore, the media like to report about
them. The media can be helpful allies in communicating public health messages. They
can be helpful allies in reminding the public of the risks and benefits of immunization.
Building a personal relationship with key health reporters will help them to understand
the public health perspective.
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 22 lists
the elements of a good media plan for communication.
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September 2014
Table 22. Media plan for communication
Database of journalists § Maintain a list of print and electronic media journalists

covering health (local, national, international) with contact
information.
§ Always use a database where updating can be done
immediately.
§ 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, for specific diseases, and for AEFI
§ Fact sheet or a technical brief on a specific VPD, including
the burden of the disease, 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
ministry.
The information package needs to be updated regularly.
Media releases Must specifically answer the 6 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
media characteristics community than national media.
§ National media have a wide reach and influence national
agendas.
§ International media can influence national agendas.
Spokesperson system: § Identify in advance an appropriate spokesperson (or several
spokespersons in the different agencies).
§ Share contact details of spokesperson(s) with all
relevant focal points at different levels of programme
implementation.
§ Ensure the spokesperson(s) has experience or some
training in dealing with the media.
Other tips to keep in mind
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.
At the end of the press conference, advise that a further conference will be held within
a day or so, at which time full details of the event and the investigation will be provided.
A media or press conference requires expert planning and expert communications input
96
to ensure that messages are clear and unambiguous and that all expert spokespersons
are well prepared.
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.
10.3 Preparing key messages
Messages should be as simple as possible. Use simple words and short sentences. It
is helpful to tell a story, if possible. Create a “word picture” (a graphic or vivid verbal
description) to get the message across. The key messages should be kept to a minimum
and should include some of these facts:
n The benefit of immunization in preventing certain diseases is well proven. VPDs

caused millions of deaths and a huge amount of disability before the introduction
of vaccines, and that situation would return without continued use of vaccines.
n It is risky not to immunize (risk of disease and complications).
n Vaccines may/do cause reactions, but these are rarely serious.
n Immunization safety is of paramount importance and maintaining confidence in
immunization programmes depends on it.
n Any suspicion of a problem is investigated (an advantage of well established
immunization safety surveillance). This investigation is an example of such an action
being taken.
There are many sources of key messages such as these. They should be consulted and
tailored to the local culture and understanding
It is rarely necessary to suspend an immunization programme during an investigation

unless it is obvious that there is a problem with the vaccine that warrants such drastic
steps. The vast majority of situations prove to be coincidental or due to a very localized
problem (depending on the type of event), and the immunization programme must
continue to keep the population safe from disease.
Preparing a press statement
All the information to be conveyed in a media conference should be prepared in

advance and included in a press statement/press release. An effective press statement/
press release must specifically answer the six Ws and should include a one-page (400-
500 words maximum) account written in short sentences outlining:
n a complete account of the event, framed in its context (e.g. an isolated event or a
cluster of AEFI, or a coincidental event);
n no technical jargon;
n an outline of actions taken or planned (such as the AEFI investigation);
n a description of the possible cause of the event;
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September 2014
n an assurance that corrective action will be taken, and what steps have already been
taken;
n reference to any relevant publication or website for further information;
n the sender’s name and spokesperson’s details;
n quotes from key officials, after seeking their permission (the quotes must be positive
and carry the key messages);
n repetition of the key message.
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 though a press
release to the media or other locally appropriate means.
10.4 Crisis management
A crisis is a situation in which a real or potential loss of confidence in the vaccine or in the
immunization programme is triggered by information about an AEFI. Crises can often be
avoided through foresight, care and training. If managed properly, the investigation and
management of a vaccine safety situation will boost public confidence and acceptance
and ultimately strengthen the immunization programme.
How does one manage a crisis?
n Anticipate. Do not wait until a crisis occurs. Prepare for the unavoidable. Develop a
good relationship with the media. Good public awareness and understanding of the
immunization programme is necessary.
n Train staff at all levels to respond adequately. Develop confidence in responding to
the public and the media (particularly the local media) properly and correctly.
n Confirm all facts and prepare (see steps for a press conference or press release)
before making any public comments.
n Prepare a plan to react to a crisis when it occurs. This has to be done in advance,
98
Summary
n Communication with parents, community, staff, other stakeholders and the media is necessary
and important.
n During communication make sure to build confidence in the immunization programme. Be aware
of the risks and benefits of immunization and the progress and findings of the investigation.
n Communication needs assurance from someone in authority with knowledge and expertise in
the subject.
n It is recommended to prepare a communication plan in advance, as this will minimize the
negative impact of AEFI-related matters.
identifying responsible persons to handle the crisis and preparing all supporting
documents and information.
Bibliography:
n Hugman B, Labadie J. Expecting the worst – anticipating, preventing, and managing
medical product and other health care crises, second edition. Uppsala: Uppsala
Monitoring Centre; 2010.
n Paling J. Strategies to help patients understand risks. BMJ. 2003;327:745–8.
n Vaccine safety events: managing the communications response. A guide for Ministry
of Health EPI managers and health promotion units. Copenhagen: World Health
Organization Regional Office for Europe; 2013 (http://www.euro.who.int/en/health-
topics/disease-prevention/vaccines-and-immunization/publications/2013/vaccine-
safety-events-managing-the-communications-response).
99
Annexes
Annex 1. Frequency of Vaccine Adverse Reactions of commonly used
vaccines
BCG Vaccine Summary DTP Vaccines Summary

Vaccine Adverse Reactions Frequency category Vaccine Adverse Reactions Frequency category
n Injection site reaction - papule, Very Common Whole cell vaccines
mild ulceration or scar n Fever 100.1 to 101 Very Common
n Local abscess, Keloid, Uncommon to Rare n Fever 101.1 to 102 Very Common
Lymphadenitis, Suppuration
n Fever > 102 Common
n Osteitis Rare to Very Rare
n Redness 1 - 20 mm Very Common
n Disseminated BCG Very Rare
n Redness > 20 mm Very Common
n Immune Reconstitution Syndrome Very Rare
n Swelling 1 - 20 mm Very Common
Inflammatory Syndrome (IRIS)
n swelling > 20 mm Very Common
n Moderate pain Very Common
Severe pain Very Common
Hepatitis A Vaccines Summary n
n Moderate fussiness Very Common

Vaccine Adverse Reactions Frequency category n Severe fussiness Very Common
n Drowsiness Very Common
n Soreness - children Very common
n Anorexia Very Common
n Soreness - adults Very common
n Vomiting Very Common
n Induration at the injection site Common
n Persistent screaming Common
n Inj. site erythema and pain after Common
n HHE Rare
booster doses in children
n Seizures Very rare
n Inj. site erythema and pain after Very common
booster doses in adults n Encephalopathy Very Rare
n Headache in children Common n Anaphylaxis Very Rare
n Headache in adults Very common
n Malaise Common
Vaccine Adverse Reactions Frequency category
n Feeding problems Common Acellular vaccines
n Fatigue, fever, diarrhoea and Common n Fever 100.1 to 101 Very Common
vomiting
n Fever 101.1 to 102 Common
n Fever > 102 Uncommon
n Redness 1 - 20 mm Very Common
Hepatitis B Vaccines Summary n Redness > 20 mm Common
n Swelling 1 - 20 mm Very Common
Vaccine Adverse Reactions Frequency category n swelling > 20 mm Common
n Pain Very common to common n Moderate pain Common
n Erythema Common n Severe pain Uncommon
n Swelling Common n Moderate fussiness Very Common
n Temperature greater than 37.7°C Common n Severe fussiness Common
n Headache Common n Drowsiness Very Common
n Anaphylaxis Very rare n Anorexia Very Common
n Vomiting Very Common
n Persistent screaming Uncommon
n HHE Rare
n Seizures Very Rare
n Encephalopathy No documented risk
n Anaphylaxis Rate undocumented
JE Vaccine Summary Hib Vaccines Summary

Vaccine type Frequency category Vaccine Adverse Reactions Frequency category
Inactivated Vero cell- derived n Fever Common
Vi-TT n Injection site reactions Very common
n Pain, redness, induration, swelling Very common
and tenderness at injection site
Pneumococcal (conjugated & unconjugated)
Rash and other skin lesions Very common
vaccines Summary
n
n Fever, headache and other mild Very common

neurological conditions Vaccine Adverse Reactions Frequency category
n Gastrointestinal disorders Very common n Injection site reactions Very common
n Acute disseminated Very rare n Fever Uncommon
encephalomyelitis (ADEM)
n Neurological events: Encephalitis, Very rare
encephalopathy, convulsions,
peripheral neuropathy, transverse Polio Vaccines Summary
myelitis and aseptic meningitis
Inactivated Mouse brain- derived Vaccine Adverse Reactions Frequency category
n Injection site reactions; Pain, Very common
redness, induration, swelling and Oral Polio Vaccine (OPV)
tenderness n VAPP
n Headache, malaise, myalgia, low- Very common to common – Recipient VAPP Very Rare
grade fever, nausea, vomiting, – Total VAPP Very Rare
abdominal pain, rash, chills and
dizziness
n Hypersensitivity reactions Very common Inactivated Polio Vaccine (IPV)
n Anaphylaxis Very rare n Injection site erythema Common
Live attenuated SA-14-14-2 n Induration Common to Very common
n Injection site reactions Very common n Tenderness Very Common
n Fever, vomiting, abnormal crying, Very common
drowsiness, appetite loss and
irritability
n Hypersensitivity reactions No reports
Live recombinant
n Injection site reactions Very common Human Papilloma Vaccines (HPV) Summary
n Fever, vomiting, abnormal crying,
drowsiness, appetite loss and Very common Vaccine Adverse Reactions Frequency category
irritability
Bivalent HPV Vaccine
n Hypersensitivity reactions No reports
n Injection site reactions, Very common
erythema, swelling
Pyrexia
Varicella Zoster Vaccines Summary n Common
n Urticaria Common
Vaccine Adverse Reactions Frequency category n Headache Very common
n Myalgia Very common
Monovalent varicella vaccine
n Arthralgia Very common
n Fever Very common
n Gastrointestinal disorders Very common
n Injection site reactions Very common to common
n Fatigue Very common
n Skin rash at injection site Common
n Rash Common
n Skin rash generalised Common
Combination MMRV Quadrivalent HPV Vaccine

n Fever Very common n Injection site reactions, Common to
n Skin rash Very common erythema, swelling very common
n Pyrexia Very Common
Monovalent varicella vaccine n Urticaria Common
n Febrile seizures (with MMR via Rare n Headache Very Common
separate injection)
n Myalgia Common
Combination MMRV n Arthralgia Common
(age 12-23 months) n Gastrointestinal disorders Very Common
n Febrile seizures Rare n Anaphylaxis Very Rare
101
September 2014
Typhoid Vaccine Summary Measles Vaccines Summary

Vaccine type Frequency category Vaccine Adverse Reactions Frequency category
Ty21a n Injection site reactions Very common
n Fever Uncommon to common n Fever Common to very common
n Vomiting Uncommon to common n Rash Common
n Diarrhoea Common n Febrile seizures Rare
n Encephalomyelitis Very rare
ViCPS n Thrombocytopenia Very rare
n Low grade fever (<39C) Common Very rare
n Anaphylaxis
n Local erythema Common to very common
n Soreness Common to very common
n Swelling Common to very common
Rubella Vaccines Summary
Vi-TT Vaccine Adverse Reactions Frequency category
n Injection site pain Only clinical trial data n Fever Common
available
n Injection site reactions Very common
n Fever Only clinical trial data
n Acute Arthralgia Very common
available
n Acute Arthritis Very common
Rotavirus Vaccines Summary Mumps Vaccines Summary
Vaccine Adverse Reactions Frequency category Vaccine Adverse Reactions Frequency category
n Injection site reactions Very common
n Intussusception Very rare with first dose;
none after subsequent n Parotid swelling Common
doses n Aseptic meningitis Very common
n Orchitis, Sensorineural deafness, Case reports
acute myositis
Key
Very common > 1/10 > 10%
Common > 1/100 and < 1/10 > 1% and < 10%
Uncommon > 1/1,000 and < 1/100 > 0.1% and < 1 %
Rare > 1/10,000 and < 1/1,000 > 0.01% and < 0.1%
Very rare < 1/10,000 < 0.01%
Source: WHO Fact sheets www/who.int/vaccines safety/initiative/tools/vaccinfosheets
102
Annex 2. AEFI Reporting Form AEFI reporting id number:
REPORTING FORM FOR ADVERSE EVENTS FOLLOWING IMMUNIZATION (AEFI)
*Patient Name: *Reporter’s Name:

*Patient’s full Address: Institution:
Designation & Department:
Telephone: Address:
Sex: M F
*Date of birth : _ _/ __/ __ Telephone & E-mail:

OR Age at onset: Years Months Days Date patient notified event to health system: __/ __/ __
OR Age Group at onset: <1 Year 1 to 5 Years >5 Years Today’s date : _ _/ __/ __
Health facility (place or vaccination centre) name & address:

Vaccine Diluent (if applicable)
*Name of vaccine *Date of *Time of Dose *Batch /Lot Expiry Name of *Batch /Lot Expiry Date and time
vaccination vaccination (1st, 2nd, number date diluent number date of
etc.) reconstitution
*Adverse event(s):
Date AEFI started : __/ __/ __
Severe local reaction >3 days beyond nearest joint
Time __ __ __ __
Seizures febrile afebrile
Describe AEFI (Signs & Symptoms):
Abscess
Sepsis
Encephalopathy
Toxic shock syndrome
Thrombocytopenia
Anaphylaxis
Fever ≥38°C
Other (specify)................................................................
*Serious: Yes / No;  If Yes Death Life threatening Persistent or significant disability Hospitalization Congenital anomaly
Other important medical event (specify).................................................................................................
*Outcome: Recovering Recovered Recovered with sequelae Not Recovered Unknown
Died If Died, date of death : _ _/ __/ __ Autopsy done: Yes No Unknown
Past medical history (including history of similar reaction or other allergies), concomitant medication and other relevant information
(e.g. other cases). Use additional sheets if needed :
First Decision making level to complete:

Investigation needed: Yes No If Yes, date investigation planned : __/ __/ __
National level to complete:
Date report received at National level _ _/ __/ __ AEFI worldwide unique ID :
Comments:
*Compulsory field - 103 - 103

September 2014
Annex 3. AEFI Investigation Form

AEFI INVESTIGATION FORM
(Only for Serious Adverse Events Following Immunization − Death / Disability / Hospitalization / Cluster)
Section A Basic details
Province/State District Case ID
Place of vaccination (): Govt. health facility Private health facility Other (specify) _________
Vaccination in (): Campaign Routine Other (specify) _________
Address of vaccination site:
Date of investigation: __ __ / __ __ / __ __ __ __
Name of Reporting Officer:
Date of filling this form: __ __ / __ __ / __ __ __ __
Designation / Position: This report is: First Interim Final
Telephone # landline (with code): Mobile: e-mail:
Patient Name Sex: M F
(use a separate form for each case in a cluster)
Date of birth (DD/MM/YYYY): __ __ / __ __ / __ __ __ __
OR Age at onset: __ __ years __ __ months __ __ __ days OR Age group: < 1 year 1−5 years > 5 years
Patient’s full address with landmarks (Street name, house number, locality, phone number etc.):
Name of
Time of Dose Expiry date
vaccines/diluent Date of vaccination st nd Batch/Lot number
vaccination (e.g. 1 , 2 , etc.)
received by patient
Vaccine Vaccine
Diluent Diluent
Vaccine Vaccine
Diluent Diluent
Vaccine Vaccine
Diluent Diluent
Vaccine Vaccine
Diluent Diluent
Vaccine Vaccine
Diluent Diluent
Type of site () Fixed Mobile Outreach Other ___________
Date of first/key symptom (DD/MM/YYYY): __ __ / __ __ / __ __ __ __ Time of first symptom (hh/mm): __ __ / __ __

Date of hospitalization (DD/MM/YYYY): __ __ / __ __ / __ __ __ __
Date first reported to the health authority (DD/MM/YYYY): __ __ / __ __ / __ __ __ __
Status on the date of investigation (): Died Disabled Recovering Recovered completely Unknown
If died, date and time of death (DD/MM/YYYY): __ __ / __ __ / __ __ __ __ (hh/mm): __ __ / __ __

Autopsy done? () Yes (date)_______________ No Planned on (date)_____________ Time__________
Attach report (if available)
Section B Relevant patient information prior to immunization

Criteria Finding Remarks (If yes provide details)
Past history of similar event Yes / No / Unkn
Adverse event after previous vaccination(s) Yes / No / Unkn
History of allergy to vaccine, drug or food Yes / No / Unkn
Pre-existing illness (30 days) / congenital disorder Yes / No / Unkn
History of hospitalization in last 30 days, with cause Yes / No / Unkn
Patient currently on concomitant medication? Yes / No / Unkn
(If yes, name the drug, indication, doses & treatment dates)
Family history of any disease (relevant to AEFI) or allergy Yes / No / Unkn
For adult women
• Currently pregnant? Yes (weeks) ______________________ / No / Unknown
• Currently breastfeeding? Yes / No
For infants
The birth was full-term pre-term post-term. Birth weight:
Delivery procedure was Normal Caesarean Assisted (forceps, vacuum etc.) with complication (specify)
104 - 104 -
.
Name Case ID Number AEFI Investigation Page 2/4
Section C Details of first examination** of serious AEFI case
Source of information ( all that apply): Examination by the investigator Documents Verbal autopsy
Other____________________________ If from verbal autopsy, please mention source ____________________________
Name of the person who first examined/treated the patient:____________________________
Name of other persons treating the patient: _________________________________
Other sources who provided information (specify): ______________________________
Signs and symptoms in chronological order from the time of vaccination:
Name and contact information of person completing Designation: Date/time

these clinical details:
**Instructions – Attach copies of ALL available documents (including case sheet, discharge summary, case notes,
laboratory reports and autopsy reports) and then complete additional information NOT AVAILABLE in existing
documents, i.e.
• If patient has received medical care − attach copies of all available documents (including case sheet, discharge
summary, laboratory reports and autopsy reports, if available) and write only the information that is not available in the
attached documents below
• If patient has not received medical care – obtain history, examine the patient and write down your findings below (add
additional sheets if necessary)
Provisional / Final diagnosis:
- 105 - 105
September 2014
.
Section D Details of vaccines provided at the site linked to AEFI on the corresponding day
Number immunized Vaccine

for each antigen at name
session site. Attach
Number
record if available.
of doses
a) When was the patient immunized? ( the below and respond to ALL questions)
Within the first vaccinations of the session Within the last vaccinations of the session Unknown
In case of multidose vials, was the vaccine given within the first few doses of the vial administered? within the
last doses of the vial administered? unknown?
b) Was there an error in prescribing or non-adherence to recommendations for use of this
Yes∗ / No
vaccine?
c) Based on your investigation, do you feel that the vaccine (ingredients) administered could have Yes∗ / No / Unable to
been unsterile? assess
d) Based on your investigation, do you feel that the vaccine's physical condition (e.g. colour, Yes∗ / No / Unable to
turbidity, foreign substances etc.) was abnormal at the time of administration? assess
e) Based on your investigation, do you feel that there was an error in vaccine
Yes∗ / No / Unable to
reconstitution/preparation by the vaccinator (e.g. wrong product, wrong diluent, improper
assess
mixing, improper syringe filling etc.)?
f) Based on your investigation, do you feel that there was an error in vaccine handling (e.g. Yes∗ / No / Unable to
break in cold chain during transport, storage and/or immunization session etc.)? assess
g) Based on your investigation, do you feel that the vaccine was administered incorrectly (e.g.
Yes∗ / No / Unable to
wrong dose, site or route of administration, wrong needle size, not following good injection
assess
practice etc.)?
h) Number immunized from the concerned vaccine vial/ampoule
i) Number immunized with the concerned vaccine in the same session
j) Number immunized with the concerned vaccine having the same batch number in other
locations. Specify locations: _____________
k) Is this case a part of a cluster? Yes∗ / No / Unkn
i. If yes, how many other cases have been detected in the cluster?
a.Did all the cases in the cluster receive vaccine from the same vial? Yes∗ / No / Unkn
b.If no, number of vials used in the cluster (enter details separately)
∗
It is compulsory for you to provide explanations for these answers separately
Section E Immunization practices at the place(s) where concerned vaccine was used
(Complete this section by asking and/or observing practice)
Syringes and needles used:
• Are AD syringes used for immunization? Yes / No / Unkn
If no, specify the type of syringes used: Glass Disposable Recycled disposable Other _______
Specific key findings/additional observations and comments:
Reconstitution: (complete only if applicable,  NA if not applicable)

• Reconstitution procedure () Status
Same reconstitution syringe used for multiple vials of same vaccine? Yes No NA
Same reconstitution syringe used for reconstituting different vaccines? Yes No NA
Separate reconstitution syringe for each vaccine vial? Yes No NA
Separate reconstitution syringe for each vaccination? Yes No NA
• Are the vaccines and diluents used the same as those recommended by the manufacturer? Yes No NA
106 - 106 -
.
Section F Cold chain and transport

(Complete this section by asking and/or observing practice)
Last vaccine storage point:
• Is the temperature of the vaccine storage refrigerator monitored? Yes / No
°
o If “yes”, was there any deviation outside of 2−8 C after the vaccine was placed inside? Yes / No
o If “yes”, provide details of monitoring separately.
• Was the correct procedure for storing vaccines, diluents and syringes followed? Yes / No / Unkn
• Was any other item (other than EPI vaccines and diluents) in the refrigerator or freezer? Yes / No / Unkn
• Were any partially used reconstituted vaccines in the refrigerator? Yes / No / Unkn
• Were any unusable vaccines (expired, no label, VVM at stages 3 or 4, frozen) in the refrigerator? Yes / No / Unkn
• Were any unusable diluents (expired, manufacturer not matched, cracked, dirty ampoule) in the store? Yes / No / Unkn
Vaccine transportation:
• Type of vaccine carrier used
• Was the vaccine carrier sent to the site on the same day as vaccination? Yes / No / Unkn
• Was the vaccine carrier returned from the site on the same day as vaccination? Yes / No / Unkn
• Was a conditioned ice-pack used? Yes / No / Unkn
Section G Community investigation (Please visit locality and interview parents/others)
Were any similar events reported within a time period similar to when the adverse event occurred and in the same locality?
Yes / No / Unknown If yes, describe:
If yes, how many events/episodes?
Of those effected, how many are

• Vaccinated:_____________________________
• Not vaccinated:__________________________
• Unknown:________________________________
Other comments:
Section H Other findings/observations/comments
- 107 - 107
September 2014
Annex 4. AEFI Line listing
Name/ID
Village/Town/District
Date of birth (dd/mm/yyyy) and age
Date of immunization(dd/mm/yyyy)
Reaction type (code) [1] Minor [2] Severe/Serious
Outcome (Recovered disability/Died)
Suspect vaccine (name and dose, e.g. Penta-2)
Vaccine batch/Lot number
Diluent batch number
Onset time interval (hours, days, weeks)
Date reporting (dd/mm/yyyy)
Investigated? (If yes, date)
Final diagnosis
Cause (code)
Establishing codes for area, reaction type, cause of AEFI, and certainty of cause will facilitate recording, data entry and analysis.
Because of the potential for coding errors, the code should be double-checked.
Coding for cause of AEFI:
[A1] [A2] [A3] [B] [C] [D]
Vaccine-related Immunization error- Immunization anxi- Indeterminate Coincidental Inadequate

related ety-related information to
classify
108 - 108 -
Annex 5. Causality Assessment: Step 2 (Event Checklist)

[4 (check) all boxes that apply]
I. Is there strong evidence for other causes? Y N UK NA Remarks
Does clinical examination, or laboratory tests on the patient, confirm
another cause? r r r r
II. Is there a known causal association with the vaccine or vaccination?
Vaccine product(s)
Is there evidence in the literature that this vaccine(s) may cause the
reported event even if administered correctly? r r r r
Did a specific test demonstrate the causal role of the vaccine or any of
the ingredients? r r r r
Immunization error
Was there an error in prescribing or non-adherence to
recommendations for use of the vaccine (e.g. use beyond the expiry r r r r
date, wrong recipient etc.)?
Was the vaccine (or any of its ingredients) administered unsterile? r r r r
Was the vaccine’s physical condition (e.g. colour, turbidity, presence of
foreign substances etc.) abnormal at the time of administration? r r r r
Was there an error in vaccine constitution/preparation by the vaccinator
(e.g. wrong product, wrong diluent, improper mixing, improper syringe r r r r
filling etc.)?
Was there an error in vaccine handling (e.g. a break in the cold chain
during transport, storage and/or immunization session etc.)? r r r r
Was the vaccine administered incorrectly (e.g. wrong dose, site or route
of administration; wrong needle size etc.)? r r r r
Immunization anxiety
Could the event have been caused by anxiety about the immunization
(e.g. vasovagal, hyperventilation or stress-related disorder)? r r r r
II (time). If “yes” to any question in II, was the event within the time window of increased risk?
Did the event occur within an appropriate time window after vaccine
administration? r r r r
III. Is there strong evidence against a causal association?
Is there strong evidence against a causal association? r r r r
IV. Other qualifying factors for classification
Could the event occur independently of vaccination (background rate)? r r r r
Could the event be a manifestation of another health condition? r r r r
Did a comparable event occur after a previous dose of a similar
vaccine? r r r r
Was there exposure to a potential risk factor or toxin prior to the event? r r r r
Was there acute illness prior to the event? r r r r
Did the event occur in the past independently of vaccination? r r r r
Was the patient taking any medication prior to vaccination? r r r r
Is there a biological plausibility that the vaccine could cause the event? r r r r
Y: Yes. N: No. UK: Unknown. NA: Not applicable.
- 109 - 109

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WHO Library Cataloguing-in-Publication Data

Global manual on surveillance of adverse events following immunization.

ISBN 978 92 4 150776 9 (NLM classification: WA 115)

© World Health Organization 2014 (Revised March 2016)

Printed by the WHO Document Production Services, Geneva, Switzerland.

Cover by Denis Meissner-WHO - Layout by Jean-Claude Fattier

2.3 Contraindications and precautions................................................................ 10

7. Analysis of AEFI data....................................................................................... 63

Annex 1. Frequency of Vaccine Adverse Reactions of commonly used vaccines...... 100

Figure 1 Programme implementation level, responsibility and surveillance activities

Adverse event Any untoward medical occurrence which follows

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

Causality assessment In the context of AEFI surveillance, causality assessment is

Cluster Two or more cases of the same or similar events related in

Contraindication A situation where a particular treatment or procedure,

Immunity The ability of the human body to tolerate the presence of

Immunization safety The process of ensuring the safety of all aspects of

Immunization safety A system for ensuring immunization safety through

Serious AEFI An event that results in death, is life-threatening, requires

Surveillance The continuing, systematic collection of data that are

Trigger event A medical incident following immunization that stimulates a

Vaccine A biological preparation that improves immunity to a

Vaccine The science and activities relating to the detection,

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

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

Vaccination failure* Vaccination failure may be defined on the basis of clinical

Vaccine reaction An event caused or precipitated by the active component

AEFI Adverse event following immunization

BCG Bacillus Calmette-Guerin vaccine for tuberculosis (TB)

CIOMS Council for International Organizations of Medical Sciences

DTP Diphtheria-tetanus-pertussis vaccine

DTaP Diphtheria-tetanus-pertussis (acellular) vaccine

DTwP Diphtheria-tetanus-pertussis (whole-cell) vaccine

EPI Expanded Programme on Immunization

HHE Hypotonic hyporesponsive episode

Hib Haemophilus influenzae type b vaccine

ICH International Conference on Harmonization

IPV Inactivated poliovirus vaccine

LAV Live attenuated vaccine

MMR Measles-mumps-rubella vaccine

NRA National regulatory authority

NCL National control laboratory

OPV Oral poliovirus vaccine

PCV Pneumococcal conjugate vaccine

PvV Pentavalent (DTP-HepB-Hib) vaccine

TSS Toxic shock syndrome

VAPP Vaccine-associated paralytic poliomyelitis

VPD Vaccine-preventable disease

WHO World Health Organization

Vaccines rarely cause serious adverse reactions, and

n strategies and systems for ensuring quality and safety of vaccines;

Who will use this manual?

This manual will be useful for immunization programme managers, staff

2.1.1 Active immunity

2.1.2 Passive immunity

Passive artificial immunity provides only temporary protection against infection – as

2.1.3 Herd immunity

2.1.4 How does immunization work?

Subsequent administration of the same vaccine stimulates the secondary immune