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Transcript of Immunization Safety Surveillance
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Immunization Safety SurveillanceGuidelines for immunization programme managers
on surveillance of adverse events following immunization
Second Edition
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Immunization Safety Surveillanceiiii
WHO Library Cataloguing in Publication Data
Immunizatin saety surveillance: guidelines r immunizatin prgramme managers n surveillance
adverse events llwing immunizatin (Secnd Editin).
1. Immunizatin. 2. Immunizatin prgrams rganizatin and administratin.3. Guidelines. 4. Saety management. 5. Vaccines - standards. I. Wrld Health Organizatin Reginal
Oce r the Western Pacic.
ISBN 978 92 9061 596 5 (NLM Classicatin: WA115)
World Health Organization 2013
All rights reserved. Publicatins the Wrld Health Organizatin can be btained rm WHO Press,
Wrld Health Organizatin, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; ax:
+41 22 791 4857; e-mail: [email protected]). Requests r permissin t reprduce r translate WHO
publicatins whether r sale r r nncmmercial distributin shuld be addressed t WHO Press,
at the abve address (ax: +41 22 791 4806; e-mail: [email protected]). Fr WHO Western Pacic
Reginal Publicatins, request r permissin t reprduce shuld be addressed t the PublicatinsOce, Wrld Health Organizatin, Reginal Oce r the Western Pacic, P.O. Bx 2932, 1000, Manila,
Philippines, (ax: +632 521 1036, e-mail: [email protected]).
Te designatins emplyed and the presentatin the material in this publicatin d nt imply the
expressin any pinin whatsever n the part the Wrld Health Organizatin cncerning the legal
status any cuntry, territry, city r area r its authrities, r cncerning the delimitatin its
rntiers r bundaries. Dtted lines n maps represent apprximate brder lines r which there may
nt yet be ull agreement.
Te mentin specic cmpanies r certain manuacturers prducts des nt imply that they
are endrsed r recmmended by the Wrld Health Organizatin in preerence t thers a similar
nature that are nt mentined. Errrs and missins excepted, the names prprietary prducts aredistinguished by initial capital letters.
All reasnable precautins have been taken by the Wrld Health Organizatin t veriy the inrmatin
cntained in this publicatin. Hwever, the published material is being distributed withut warranty
any kind, either expressed r implied. Te respnsibility r the interpretatin and use the material
lies with the reader. In n event shall the Wrld Health Organizatin be liable r damages arising rm
its use.
Images used in cver curtesy WHO
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iiiTable of Contents
Table of Contents
Preface vi
Glossary vii
Abbreviations ix
Purpose 1
Principles of immunization and vaccine 3
Immunity 3
Vaccine 4
Adverse events following immunization (AEFIs) 9Vaccine reactins 10
Immunizatin errrrelated reactins 14
Immunizatin anxiety-related reactins 17
Cincidental events 18
Establishing immunization safety surveillance 22
Objectives 22
Steps r establishing a system 23
Rle and respnsibility NRA in immunizatin saety surveillance 24
Rle and respnsibility immunizatin prgramme (manager) in immunizatin saety
surveillance 25erms Reerence (OR) the Natinal Immunizatin Saety Expert Cmmittee 30
Dierences between surveillance AEFIs and adverse events t drugs 32
raining pprtunities r vaccine saety 32
Reporting AEFIs 35
Which events shuld be reprted? 35
When t reprt? 37
Hw t reprt? 37
Reprting AEFIs during immunizatin campaigns 39
Barriers t reprting 39
Private sectr reprting 40
Investigating AEFIs 41
Why reprts shuld be investigated? 41
Which reprts shuld be investigated? 41
Wh shuld investigate? 42
When t investigate? 42
Hw t investigate? 42
Investigating AEFI clusters 46
Investigatin deaths 47
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Immunization Safety Surveillanceiviv
Analysis of AEFI data 48
Wh shuld analyse the data? 48
Hw shuld the data be analysed and interpreted? 49
Purpse analysis at dierent levels 52
Hw shuld a cause be determined? 53
Causality assessment of AEFI 54
Levels AEFI causality assessment and their scientic basis 54
Case selectin r AEFI causality assessment 55
Prerequisites r AEFI causality assessment 56
Causality assessment methd 56
Actions and follow-up to AEFIs 61
Crrective actins 61
raining and awareness 63
Communication 64
Cmmunicatin with parents and cmmunity 64
Cmmunicatin with health sta 65
Cmmunicating with stakehlders 65
Cmmunicating with the media 65
Crisis management 69
Evaluation of the immunization safety surveillance system 71
References 73
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vTable of Contents
Annex A: Websites n vaccine saety 76
Annex B: AEFI case denitins and treatment 77
Annex C: Recgnitin and treatment anaphylaxis 81
Annex D: Vaccine preventable diseases (VPD) risks 86
Annex E: NRA indicatrs assessing pharmacvigilance including AEFI surveillance 91
Annex F: Reprting Frm r Adverse Events Fllwing Immunizatin (AEFI) 94
Annex F1:Prpsed detailed cre variables required reprting in AEFI surveillance 95
Annex G: Adverse Events Fllwing Immunizatin Case Investigatin Frm 96
Annex H: AEFI line listing 97
Annex I: AEFI Causality Assessment Step 2: Event checklist 98
Annex J: Checklist r immunizatin saety surveillance system 99
List of annexes
List of tables and gures
able 1: Causespecic categrizatin AEFIs (CIOMS/WHO 2012) 9
able 2: Cmmn, minr vaccine reactins and treatment 11
able 3: Rare vaccine reactins, nset interval and rates 13
able 4: Immunizatin errr-related reactins 15
able 5: Estimated cincidental deaths temprally linked t DP
immunizatin in selected cuntries in the Western Pacic Regin 20able 6: Prgramme implementatin level, respnsibility
and purpse surveillance 28
able 7: List reprtable AEFIs 36
able 8: Cre variables with minimum inrmatin required
reprting in AEFI surveillance 38
able 9: Steps in an AEFI investigatin 44
able 10: Labratry testing t investigate AEFIs by wrking hypthesis 45
able 11: Guide t specimen samples btained llwing selected AEFIs 45
able 12: Actins t saeguard the public during an investigatin 61
able 13: Actins t be taken upn cmpletin the investigatin 62
Figure 1: Glbal Vaccine Saety Resurce Centre 33
Figure 2: Identiying cause AEFI cluster 47
Figure 3: WPRO calculatr r expected vaccine reactin rates 50
Figure 4: Causality assessment: Eligibility 57
Figure 5: Causality assessment: Checklist (main subdivisins) 58
Figure 6: Causality assessment: Algrithm 58
Figure 7: Causality assessment: Classicatin 59
Figure 8: Causality assessment an individual case vs. a cluster/signal 60
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Immunization Safety Surveillancevivi
Preface
Tis dcument aims t assist managers in immunizatin prgramme and natinal regulatryauthrities t establish/strengthen immunizatin saety surveillance system.
Te rst Reginal Immunizatin Saety Surveillance: Guidelines r Managers Immunizatin
Prgrammes n Reprting and Investigating Adverse Events Fllwing Immunizatin was
published in 1999. Over the llwing decade, signicant develpments had been made
in the eld immunizatin saety, bth in knwledge and practices. In 2012, Expanded
Prgramme n Immunizatin (EPI), at the WHO Reginal Oce r the Western
Pacic, tk initiative r an extensive revisin the guidelines t include all updated
inrmatin. Dr Ananda Amarasinghe, Dr Md. Shaqul Hssain, Dr Sat Yshikuni and
Dr Sergey Dirditsa reviewed and revised the guidelines.
Te writers acknwledge the supprt rm ther team members EPI unit and EPI cal pints
at cuntry levels in the Western Pacic Regin. Tey are als grateul r valuable cmments
and supprt received rm Glbal Vaccine Saety team members WHO Headquarters as well
as rm ther partners.
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viiGlossary
Glossary
Adverse event llwingimmunizatin (AEFI)
Any untward medical ccurrence which llws immunizatinand which des nt necessarily have a causal relatinship with the
usage the vaccine. Te adverse event may be any unavurable r
unintended sign, abnrmal labratry nding, symptm r disease.
Causal assciatin/link An AEFI which is caused by administratin a particular vaccine.
Causally assciated events are als temprally assciated (i.e. they
ccur within a limited time perid aer vaccine administratin),
but events which are temprally assciated may nt necessarily be
causally assciated.
Cluster w r mre cases the same r similar events related in time,gegraphy, and/r vaccine administered. Natinal prgramme
managers may decide upn a mre precise denitin.
Cincidental adverse
events
A medical event that ccurs aer immunizatin, but is nt
caused by the vaccine. It wuld have ccurred whether r nt the
individual had received an immunizatin prir t the event. Tis
ccurs due t a chance tempral assciatin.
Injectin saety Te public health practices and plicies dealing with varius aspects
the use injectins (including adequate supply, administratin
and waste dispsal) s that the risk transmissin bldbrnepathgens is minimized. All injectins, irrespective their
purpse, are cvered by this term (see denitin sae injectin
practices).
Immunizatin saety Te public health practices and plicies dealing with the varius
aspects the crrect administratin vaccines, cussing n
minimizing the risk transmissin disease with the injectin
and maximizing the eectiveness the vaccine. Te term
encmpasses the spectrum events rm prper manuacture t
crrect administratin.
Immunizatin saety
surveillance
A system r ensuring immunizatin saety thrugh detecting,
reprting, investigating, and respnding t AEFIs.
Minr AEFI An event that is nt serius and des nt pse a ptential risk t
the health the recipient.
Sae injectin practice Tse public health practices and plicies which ensure that the
prcess injectin carries the minimum risk, regardless the
reasn r the injectin r the prduct injected.
Serius AEFI An event that is causing a ptential risk t the health/lie a
recipient leading t hspitalizatin, disability/incapacity, cngenital
abnrmalities/birth deects r death.
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Immunization Safety Surveillanceviiiviii
Surveillance Te cntinuing, systematic cllectin data that are analysed and
disseminated t enable decisin-making and actin t prtect the
health ppulatins.
rigger event A medical incident llwing immunizatin that stimulates a
respnse, usually a case investigatin.
Vaccine Bilgical substance that is administered t individuals t elicit
immunity (prtectin) against a specic disease.
Vaccine
pharmacvigilance
Te science and activities relating t the detectin, assessment,
understanding and cmmunicatin AEFIs and ther vaccine- r
immunizatin-related issues, and t the preventin untward
eects the vaccine r immunizatin.
Vaccine reactin An event caused r precipitated by the active cmpnent r ne the ther cmpnents the vaccine (e.g. adjuvant, preservative r
stabilizer). Tis is due t inherent prperties the vaccine.
Vaccinatin ailure Vaccinatin ailure may be dened n the basis clinical endpints
r immunlgical criteria where crrelates r surrgate markers r
disease prtectin exist. Primary ailure (e.g. lack sercnversin
r serprtectin) needs t be distinguished rm secndary ailure
(waning immunity).
Vaccinatin ailure can be due t (i) vaccine ailure, r (ii) ailure
t vaccinate, i.e. an indicated vaccine was nt administered
apprpriately r any reasn.
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ixAbbreviations
Abbreviations
AEFI adverse event llwing immunizatin
BCG bacillus Calmette-Guerin vaccine r tuberculsis (B)
CFR case-atality rate
CIOMS Cuncil r Internatinal Organizatins Medical Sciences
CISA Clinical Immunizatin Saety Assessment Netwrk
CNS central nervus system
CRS cngenital rubella syndrme
D diphtheria-tetanus vaccine
DP diphtheria-tetanus-pertussis vaccine
DaP diphtheria-tetanus-pertussis (acellular) vaccine
DwP diphtheria-tetanus-pertussis (whle-cell) vaccine
EPI Expanded Prgramme n Immunizatin
GI gastrintestinal tract
HCC hepatcellular carcinma
Hib Haemphilus infuenzae type b vaccine
HPV human papillma virus
ICH Internatinal Cnerence n Harmnizatin
IPV injectable pli vaccine
MMR measles-mumps-rubella vaccine
MR measles-rubella vaccine
NRA natinal regulatry authrity
NCL natinal cntrl labratry
OPV ral plimyelitis vaccine
PCV pneumcccal cnjugate vaccinePMS pst-marketing surveillance
PvV pentavalent (DP-HepB-Hib) vaccine
SSPE subacute sclersing panencephalitis
d adult tetanus-diphtheria vaccine
SS txic shck syndrme
VAPP vaccine-assciated paralytic plimyelitis
VPD vaccine preventable disease
WHO Wrld Health Organizatin
WPR Western Pacic Regin
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Immunization Safety Surveillancex
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Purpose 1
Purpose
he gal immunizatin is t prtect the individual and the public rm vaccine
preventable diseases (VPD). Althugh mdern vaccines are sae, n vaccine is
entirely withut risk; adverse reactins will ccasinally ccur llwing vaccinatin.
Sme peple experience adverse events aer immunizatin ranging rm mild side-eects
t rare lie-threatening illnesses. In the majrity serius cases these events are merely
cincidences. In thers, they are caused by the vaccine r by an errr in the administratin
r handling the vaccine. Smetimes there is n causal relatinship between the vaccineand the adverse eects. Maintaining public trust in vaccine saety, therere, is key t the
success all vaccinatin prgrammes.
Irrespective the cause, when adverse events llwing immunizatin (AEFIs) ccur, peple
becme cnused t the extent that they reuse urther immunizatin their children,
making the children susceptible t VPDs which are mre disabling and lie-threatening.
Surveillance AEFIs, i.e. systematic cllectin data n events llwing immunizatin,
prvides valuable inrmatin t help plan and take necessary actins in rder t sustain
public cndence and ensure smth unctining the prgramme.
Tis dcument prvides guidelines r managers immunizatin prgrammes (and thersrespnsible r vaccine saety and quality) n the llwing:
strategiesandsystemsforensuringqualityandsafetyofvaccines,
newclassicationofAEFIsandtheobjectivesofimmunizationsafety/AEFIs
surveillance,
understandingvaccinereactionsforbetterdecision-making,
AEFIsurveillancesystem:reporting,investigating,causalityassessmentand
respnding prcesses,
bestuseofsurveillancedata,and
communicationstrategyonimmunizationsafetyforthepublicandthemedia.
As VPDs becme less visible thrugh eective immunizatin prgrammes, mre attentin
will be given t AEFIs. A gd example is plimyelitis. When there are many cases
plimyelitis in the cmmunity, the very lw risk (abut 1 in 3 millin) vaccine-
assciated paralytic plimyelitis (VAPP) is unlikely t cause a majr cncern. Western
Pacic Regin has been ree rm pli since 2000. In cuntries where there is n lnger
any wild plivirus existent, VAPP have becme mre visible. As a result, VAPP has becme
a sucient cncern and these cuntries have switched rm ral (OPV) t injectable
plimyelitis vaccine (IPV).
As technlgy cntinues t imprve with time, s d the quality, ecacy (level prtectin) and eectiveness (disease reductin) the vaccines. New vaccines are being
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Immunization Safety Surveillance2
added t the prgramme and the schedule becmes mre tight and cngested. Instead
triple vaccine (DP), mst cuntries are nw using either tetravalent (DP-Hib r DP-
HepB) r pentavalent (DP-HepB-Hib) vaccines. Als with emerging diseases, such
as H1N1 infuenza, demand r new vaccine has increased. An increase in vaccine use
(e.g. mass immunizatin campaigns) will lead t mre vaccine reactins as well as mre
cincidental events. Immunizatin errrs (previusly knwn as prgramme errrs)
may als increase. Reprting and investigating AEFIs can be used t identiy and crrect
immunizatin errrs-related reactins and may help t distinguish a cincidental event
rm a true AEFI. Surveillance AEFIs is an eective means mnitring immunizatin
saety and it cntributes t the credibility the immunizatin prgramme. It allws r
prper management AEFIs and avids inapprpriate respnses t reprts AEFIs that
can create a sense crisis in the absence immunizatin saety surveillance.
Public alertness regarding vaccine saety has increased thrugh awareness and increased
access t inrmatin thrugh the internet. Als, the vigilance health-care prviders nvaccine saety has increased due t strengthening AEFI surveillance. As a result, mre
cncerns n quality and saety vaccine are highlighted and/r demanded by service
prviders and the public. With this increasing cmplexity in the immunizatin cntext, t
determine whether a vaccine is causally linked t an AEFI r the AEFI is a mere cincidence
requires detailed investigatin and causality assessment.
In rder t maintain and imprve public cndence in natinal immunizatin prgrammes,
all health-care prviders shuld be cmprehensively aware all aspects AEFIs and remain
prepared t respnd t public cncerns at any time. imely respnse t public cncerns
abut the saety vaccines as well as prmpt cmmunicatin will prtect the public
and preserve the integrity the immunizatin prgramme. Aer recgnizing the need
r such a cncerted actin n vaccine saety, WHO cnducted a landscape analysis. Te
analysis prvides an verview existing structures, activities and needs vaccine saety
stakehlders and initiatives at natinal and internatinal levels. Based n the landscape
analysis, the Glbal Vaccine Saety Blueprint, a ramewrk aiming t ptimize the saety
vaccines thrugh eective use state the art pharmacvigilance principles and methds
was develped in a cllabrative prcess. Te Blueprint suggests three strategic gals that
identiy three areas wrk at dierent levels. Te rst gal is t ensure minimal capacity in
all cuntries, the secnd t prvide enhanced capacity r specic circumstances, and the
third t establish a glbal supprt netwrk.Cuntries in the Western Pacic Regin represent vast dierences in demgraphic, sci-
ecnmic and gegraphic status. Immunizatin service unctins in the Regin t
demnstrate a signicant variance in capacities. Several vaccines are used, and the capacity
r immunizatin saety surveillance is generally varied. It is hped that these guidelines will
help cuntries in the Regin t either adapt them with necessary mdicatins r use them
as they are t develp a cuntry-specic immunizatin saety/AEFIs surveillance guideline.
Te gals these guidelines are t imprve eciency surveillance activities AEFIs
and t imprve the quality immunizatin services at the cuntry and reginal levels, and,
nally, t ensure immunizatin saety all recipients vaccines leading twards achieving
the gals and bjectives the immunizatin prgramme glbally.
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Principals of immunization and vaccine 3
Principles of immunizationand vaccine
Immunity
Immunity is the ability the human bdy t tlerate the presence material indigenus
t the bdy (sel) and t eliminate reign (nn-sel) material. Tis discriminatry
ability prvides prtectin rm inectius diseases, since mst micrbes are identied as
reign by the immune system. Immunity t a micrbe is usually indicated by the presence
antibdy t that rganism. Immunity is generally very specic t a single rganism r a
grup clsely-related rganisms.
Tere are tw basic mechanisms r acquiring immunity: active and passive.
Active immunity
Active immunity is stimulatin the immune system t prduce antigen-specic humral
(antibdy) and cellular immunity. Usually it lasts r many years, en a lietime. One way
t acquire active immunity is t survive inectin with the disease-causing rm the
rganism. Upn re-expsure t the same antigen, these memry cells begin t replicate and
prduce antibdy very rapidly t re-establish prtectin.
Anther way t prduce active immunity is by vaccinatin. Vaccines interact with the
immune system and en prduce an immune respnse similar t that prduced by the
natural inectin, but they d nt subject the recipient t the disease and its ptential
cmplicatins.
Many actrs may infuence the immune respnse t vaccinatin. Tese include the presence
maternal antibdy, nature and dse antigen, rute administratin, and the presence
an adjuvant (e.g. aluminium cntaining material) added t imprve the immungenicity
the vaccine. Hst actrs such as age, nutritinal actrs, genetics and cexisting disease
may als aect the respnse.
Passive immunity
Passive immunity is the transer antibdy prduced by ne human r animal t anther.
Passive immunity prvides prtectin against sme inectins, but this prtectin is
temprary. Te antibdies degrade ver time. Te mst cmmn rm passive immunity
is that which an inant receives rm its mther. Te antibdies received rm the mther
prtect the inant rm certain diseases r up t a year.
Herd immunity
Herd immunity (r cmmunity immunity) describes a type immunity that ccurs when
the vaccinatin a prtin the ppulatin (r herd) prvides prtectin t unprtected
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Immunization Safety Surveillance44
individuals. Herd immunity thery prpses that in diseases passed rm individual t
individual it is dicult t maintain a chain inectin when large numbers a ppulatin
are immune. Te higher the number immune individuals, the lwer the likelihd that a
susceptible persn will cme int cntact with an inectius agent. Frm bth theretical and
practical perspectives, disease usually disappears bere immunizatin levels reach 100%,
as has been seen with smallpx and plimyelitis. Te prprtin immune individuals in
a ppulatin abve which a disease may n lnger persist is the herd immunity threshld.
Its value varies with the virulence the disease, the ecacy the vaccine, and the cntact
parameter r the ppulatin.
How does immunization work?
Tere are many types vaccines, but they all wrk in the same general way, by preparing
the immune system t attack the inectin. Basically, vaccine cntains cmpnents that are
mre r less similar t the inecting rganism, and s the immune system respnds as itwuld t an inectin with that rganism. Te mst imprtant cnsequence successul
vaccinatin is that it prduces lng-lived memry lymphcytes that respnd mre quickly
and in a mre c-crdinated way t subsequent inectins. As a result, the inectius
micrbe is destryed mre quickly. Prtectin is nt always cmplete; an inectin may nt
be always prevented but the severity the illness is usually reduced.
Te rst expsure t a vaccine stimulates the immune respnse (knwn as priming). Te
immune system takes time t respnd t the antigen by prducing antibdies and immune
cells. Initially, immunglbulin M (IgM) antibdy is prduced but this ccurs in small
amunts and des nt bind very strngly t the antigen. Aer a ew days, the immune
respnse begins t make immunglbulin G (IgG) antibdy which is mre specic t the
micrbe and lasts lnger than IgM.
Subsequent administratin the same vaccine stimulates the secndary respnse. Te
secndary respnse is much aster than the primary respnse and prduces predminantly
IgG rather than IgM. Te aim is t generate enugh immune cells and antibdies, specic t
the inectius micrbe, t prvide lng-lasting prtectin against the disease.
Vaccine
Vaccine is a bilgical prduct that imprves and enhances immunity t a given disease.
A vaccine cntains a disease-causing micrrganism, r prtin it, and is en made
rm either live-attenuated r inactivated (killed) rms the micrbe, its txin r ne
its surace prteins.
Vaccines may be mnvalent r multivalent. A mnvalent vaccine cntains a single strain
a single antigen (e.g. measles vaccine), whereas a plyvalent vaccine cntains tw r mre
strains/sertypes the same antigen (e.g. OPV).
Cmbined vaccines cntain tw r mre antigens (e.g. DwP, DP-HepB-Hib). Ptential
advantages cmbinatin vaccines include reducing the cst stcking and administering
separate vaccines, reducing the cst extra health-care visits, imprving timeliness
vaccinatin, and acilitating the additin new vaccines int immunizatin prgrammes.
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5Principals of immunization and vaccine
Ke
ypoint
No evidence exists 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. Combining
antigens usually does not increase the risk of adverse reactions andcan, in fact, lead to an overall reduction in adverse reactions.
Classication of vaccines
Tere are ur types vaccines: live-attenuated, inactivated (killed antigen), subunit
(puried antigen) and txids (inactivated txic cmpunds). Te characteristics these
vaccines are dierent, and the characteristics determine hw the vaccines wrk.
Live-attenuated vaccines (LAV)
LAV are derived rm wild, r disease-causing, virus r bacteria. Tese wild viruses r
bacteria are attenuated, r weakened, in a labratry, usually by repeated culturing. Te
resulting vaccine rganism retains the ability t replicate (grw) in the vaccinated persn
and prduce immunity, but usually des nt cause illness. Te immune respnse t a LAV
is virtually identical t that prduced by a natural inectin.
Fr LAV, the rst dse usually prvides prtectin. An additinal dse is given t ensure
sercnversin. Fr instance, 95% t 98% recipients will respnd t a single dse
measles vaccine. Te secnd dse is given t assure that nearly 100% persns are immune
(i.e. the secnd dse is insurance). Immunity llwing live vaccines is lng-lasting, and
bster dses are nt necessary, with the exceptin ral pli vaccine, which requiresmultiple dses. LAV are labile, and can be damaged r destryed by heat and light. Tey
must be handled and stred careully. Currently available LAV include measles, mumps,
rubella, varicella, yellw ever, ral pli and infuenza (intranasal). Live-attenuated
bacterial vaccines include BCG and ral typhid vaccine.
Inactivated whole-cell vaccines
Inactivated vaccines are prduced by grwing viruses r bacteria in culture media and then
inactivating them with heat r chemicals (usually rmalin). Because they are nt alive, they
cannt grw in a vaccinated individual and, therere, cannt cause the disease, even in an
immundecient persn. Inactivated vaccines are generally saer than LAV, with n risk inducing the disease. Unlike live antigens, inactivated antigens are usually nt aected by
circulating antibdy. Tey are en mre stable than LAV.
Grwing whle bacteria (e.g. whle-cell pertussis vaccine) r viruses (e.g. inactivated
plimyelitis vaccine) in culture media, then treating them with heat and/r chemicals,
prduces an inactivated, nn-viable vaccine.
Inactivated vaccines always require multiple dses. In general, the rst dse des nt
prduce prtective immunity, but nly primes the immune system. A prtective immune
respnse is develped aer multiple subsequent dses. In cntrast t live vaccines, in which
the immune respnse clsely resembles natural inectin, the immune respnse t aninactivated vaccine is mstly humral and little r n cellular immunity results. Antibdy
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Immunization Safety Surveillance66
titers against inactivated antigens diminish with time. As a result, sme inactivated vaccines
may require peridic supplemental dses t increase, r bst, antibdy titers.
Subunit vaccines
Te whle rganism is grwn in culture media and then the rganism is urther treated tpuriy nly thse cmpnents t be included in the vaccine (e.g. acellular pertussis and the
meningcccal B vaccine).
Protein-based
Subunit vaccines can be prtein-based. Fr example, the hepatitis B vaccine is made by
inserting a segment the hepatitis B virus gene int a yeast cell. Te mdied yeast cell
prduces large amunts hepatitis B surace antigen, which is puried and harvested and
used t prduce the vaccine. Te recmbinant hepatitis B vaccine is identical t the natural
hepatitis B surace antigen, but des nt cntain virus DNA and is unable t prduce
inectin. Anther prtein-based vaccine is acellular pertussis (aP) vaccine which cntainsinactivated pertussis txin (prtein).
Polysaccharide vaccines
Meningcccal and pneumcccal plysaccharide vaccines cntain the plysaccharide
cats, r capsules, encapsulated bacteria which are puried and nn-inectius.
Conjugated vaccines
Children under tw years age d nt respnd well t antigens, such as plysaccharides,
which prduce antibdies via a -cell independent mechanism. I these plysaccharide
antigens are chemically linked (cnjugated) t a prtein that -cells recgnize, then these
cnjugate vaccines can elicit strng immune respnses and immune memry in yungchildren.
Toxoid vaccines
In sme bacterial inectins (e.g. diphtheria, tetanus), the clinical maniestatins disease
are caused nt by the bacteria themselves but by the txins they secrete. xid vaccines
are prduced by puriying the txin and altering it chemically (usually with rmaldehyde).
While n lnger txic, the txid is still capable inducing a specic immune respnse
prtective against the eects the txin.
Other components in vaccines (excipients)
Adjuvant
Smetimes a substance is added t a vaccine t enhance the immune respnse by degree
and/r duratin, making it pssible t reduce the amunt immungen per dse r the
ttal number dses needed t achieve immunity. Te cmmnly used adjuvant are
aluminium salts (aluminium hydrxide, aluminium phsphate r ptassium aluminium
sulate) which primarily enhance the immune respnse t prteins. Tey have been shwn
t be sae ver several decades use. Rarely, they may cause injectin site reactins,
including subcutaneus ndules, sterile abscess, granulmatus infammatin r cntact
hypersensitivity.
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7Principals of immunization and vaccine
Antibiotics
Antibitics are used during the manuacturing phase t prevent bacterial cntaminatin
the tissue culture cells in which the viruses are grwn. Fr example, MMR vaccine and IPV
each cntains less than 25 micrgrams nemycin per dse (less than 0.000025g). Persnswh are knwn t be allergic t nemycin shuld be clsely bserved aer vaccinatin s
that any allergic reactin can be treated at nce.
Preservatives
Tese are chemicals (e.g. thimersal, rmaldehyde) added t killed r subunit vaccines
in rder t inactivate viruses, detxiy bacterial txins, and t prevent serius secndary
inectins as a result bacterial r ungal cntaminatin.
Stabilizers
cnrm prduct quality r stability, cmpunds may be added t vaccines r a variety
manuacture-related issues: cntrlling acidity (pH); stabilizing antigens thrugh necessary
steps in the manuacturing prcess, such as reeze drying; and preventing antigens rm
adhering t the sides glass vials with a resultant lss in immungenicity. Examples such
additives include ptassium r sdium salts, lactse, human serum albumin and a variety
animal prteins, such as gelatine and bvine serum albumin.
Keypoint
Excipients are added to vaccines for dierent purposes and some of
them are removed in subsequent manufacturing steps. However, minute
trace amounts may remain in the nal product. The amounts present
are only of consequence for individuals who are allergic to them.
Nte: WHO Uppsala mnitring centre is develping a vaccine dictinary with details allexcipients in vaccines available in immunizatin practices.
Contraindication and precaution
A cntraindicatin t vaccinatin is a rare cnditin in a recipient that increases the risk
r a serius adverse reactin. Ignring cntraindicatins can lead t avidable vaccine
reactins. One the wrst and mst serius vaccine reactins is anaphylaxis (Annex C).Mst cntraindicatins are temprary, and the vaccinatin can be administered later. Te
nly cntraindicatin applicable t all vaccines is a histry a severe allergic reactin aer
a prir dse vaccine r t a vaccine cnstituent.
Precautins are nt cntraindicatins, but are events r cnditins t be cnsidered in
determining i the benets the vaccine utweigh the risks (especially i the wuld be
recipient is an immuncmprmised r pregnant persn. Precautins stated in prduct
labeling can smetimes be inapprpriately used as abslute cntraindicatins, resulting in
missed pprtunities t vaccinate.
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Immunization Safety Surveillance8
Su
mmary
Immunity is described as the bodys protective ability against
disease. There are two basic mechanisms for acquiring immunity:
active and passive.
Active immunity can be either natural, following an infection, and
can last a lifetime, or through vaccination, which also lasts for a long
period.
Passive immunity also can be either natural or articial; both last
relatively for a short period.
Vaccine is a biological product that improves immunity to a given
disease and is divided into four types: live-attenuated, inactivated
whole cell (killed), subunit and toxoid.
Excipients (adjuvant, preservatives and other additives) contained
in vaccines can cause occasional reactions. Knowledge of them isimportant in immunization safety surveillance.
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Adverse events following immunization 9
Adverse events followingimmunization (AEFIs)
Vaccines used in natinal immunizatin prgrammes are extremely sae and
eective. Nevertheless, n vaccine is perectly sae and adverse events can ccur
llwing immunizatin. In additin t the vaccines themselves, the prcess
immunizatin is a ptential surce adverse events.
An AEFI is any untward medical ccurrence which llws immunizatin and which des
nt necessarily have a causal relatinship with the usage the vaccine. Te adverse event
may be any unavurable r unintended sign, abnrmal labratry nding, symptm rdisease. Reprted adverse events can either be true adverse events, i.e. really a result the
vaccine r immunizatin prcess, r cincidental events that are nt due t the vaccine r
immunizatin prcess but are temprally assciated with immunizatin.
In 2012, the Cuncil r Internatinal Organizatins Medical Sciences (CIOMS) and
WHO revised the existing classicatin relevant t cause-specic categrizatin AEFIs
and a new categrizatin has been intrduced (able 1).
Table 1: Causespecic categorization of AEFIs (CIOMS/WHO 2012)
Causespecic type of AEFI Denition
Vaccine prduct-related reactin An AEFI that is caused r precipitated by a vaccine due
t ne r mre the inherent prperties the vaccine
prduct.
Vaccine quality deect-related
reactin
An AEFI that is caused r precipitated by a vaccine
that is due t ne r mre quality deects the
vaccine prduct, including its administratin device as
prvided by the manuacturer.
Immunizatin errr-related
reactin (rmerly prgramme
errr)
Immunizatin errr-related reactin: an AEFI that is
caused by inapprpriate vaccine handling, prescribing
r administratin and thus by its nature is preventable .
Immunizatin anxiety-related
reactin
An AEFI arising rm anxiety abut the immunizatin.
Cincidental event An AEFI that is caused by smething ther than the
vaccine prduct, immunizatin errr r immunizatin
anxiety.
Note: Immunizatin as used in these denitins means the usage a vaccine r the purpse immunizing
individuals. Usage includes all prcesses that ccur aer a vaccine prduct has le the manuacturing/ packagingsite, i.e. handling, prescribing and administratin the vaccine.
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Immunization Safety Surveillance1010
Vaccine reactions
Te new cause-specic categrizatin is imprtant r decisin-making n a vaccine
prduct, since it clearly dierentiates the tw types pssible vaccine reactins. Te
rst, vaccine prduct-related reactin, is a reactin in an individuals respnse t theinherent prperties the vaccine, even when the vaccine has been prepared, handled and
administered crrectly. Te secnd, vaccine quality deect-related reactin, is the deect in
a vaccine that ccurred during manuacturing prcess. Such a deect may have an impact
n an individuals respnse and thus increase the risk adverse vaccine reactins. In early
years immunizatin prgrammes, a ew majr incidences vaccine quality deect-
related reactins were reprted (e.g. Cutter case study). Hwever, due t intrductin
imprved Gd Manuacturing Practices (GMP) since, such deects are nw very rare.
Vaccine manuacturers llw GMP, and natinal regulatry authrities (NRA) have been
strengthened by being able t avid r minimize such reactins.
Vaccine reactins may be classied int cmmn, minr reactins r rare, mre serius
reactins. Mst vaccine reactins are minr and settle n their wn. Mre serius reactins
are very rare and, in general, d nt result in lng-term prblems.
CaseStudies
I. A suspected link between Guillain-Barre Syndrome (GBS) and
vaccinations was reported in the US in 1976, during a national
campaign to vaccinate people against swine u virus. Subsequent
investigation found that vaccine recipients had a higher risk for
GBS than those who were not vaccinated (about 1 additional case
occurred per 100 000 people vaccinated). Given this association,
and the fact that the swine u disease was limited, the vaccination
programme was stopped.
Cause: Vaccine product- related reaction
Note: It is not fully understood why some people develop GBS, but it
is believed that the nerve cells are damaged by a persons immune
system. Many types of infections, and in very rare cases vaccines,
may activate the immune system to cause damage to the nerve cells.
II. In 1955, after administration of the Cutter laboratory manufactured
inactivated polio vaccine in the US, 40 000 people developed
abortive polio; 51 were permanently paralyzed and 5 died.
Investigations revealed that two production pools of 12 000 doses
contained live virus.
Cause: Vaccine quality defect-related reaction
Common, minor vaccine reactions
Te purpse a vaccine is t induce immunity by causing the recipients immune system
t react t the vaccine. Lcal reactin, ever and systemic symptms can result as part theimmune respnse. In additin, sme the vaccines cmpnents (e.g. aluminium adjuvant,
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11Adverse events following immunization
stabilizers r preservatives) can lead t reactins. A quality and sae vaccine reduces these
reactins t a minimum while prducing the best pssible immunity. Te prprtin
reactin ccurrences likely t be bserved with the mst cmmnly used vaccines and their
treatments are listed in able 2.
Table 2: Common, minor vaccine reactions and treatment
Vaccine
Local adverse
events (pain,
swelling, redness)
Fever
(> 380C)
Irritability, malaise
and systemic
symptoms
BCG1 9095% - -
Hepatitis B Adults up t 15%
Children up t 5%
16% -
Hib 515% 210% -
Infuenza inactivated 1064% 5-12%2 -
Infuenza live-attenuated - 1631% 423%
Japanese encephalitis (JE)
inactivated
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Immunization Safety Surveillance1212
Lcal reactins include pain, swelling and/r redness at the injectin site and can be expected
in abut 10% vaccinees, except r thse injected with DwP, r tetanus bsters, where
up t 50% can be aected. BCG causes a specic lcal reactin that starts as a papule (lump)
tw r mre weeks aer immunizatin, which becmes ulcerated and heals aer several
mnths, leaving a scar. Kelid (thickened scar tissue) rm the BCG lesin is mre cmmn
amng Asian and Arican ppulatins.
Systemic reactins include ever and ccur in abut 10% r less vaccinees, except r
DwP where the reactins are abut hal. Other cmmn systemic reactins (e.g. irritability,
malaise, -clur, lss appetite) can als ccur aer DwP. Fr LAV such as measles/
MMR and OPV, the systemic reactins arise rm vaccine virus inectin. Measles vaccine
causes ever, rash and/r cnjunctivitis, and aects 5-15% vaccinees. It is very mild
cmpared t wild measles. Hwever, r severely immuncmprmised individuals, it
can be severe, even atal. Vaccine reactins r mumps (partitis, swllen partid gland)
and rubella (jint pains and swllen lymph ndes) aect less than 1% children. Rubellavaccine causes symptms mre en in adults, with 15% suering rm jint pains.
Systemic reactins rm OPV aect less than 1% vaccinees with diarrhea, headache
and/r muscle pain.
It is imprtant t nte that these bserved rates are expected as vaccine reactins r respnse
t vaccine antigen. Hwever, in case any signicant increase these bserved rates r
any vaccine, an investigatin is needed t exclude pssible adverse reactin t the given
vaccine. (Tis will be described later under the cluster investigatin.)
Rare, more serious vaccine reactionsSerius and severe are en used as interchangeable terms but they are nt. An AEFI
will be cnsidered serius, i it results in death, is lie-threatening, requires in-patient
hspitalizatin r prlngatin existing hspitalizatin, results in persistent r signicant
disability/incapacity, is a cngenital anmaly/birth deect, r required interventin t
prevent permanent impairment r damage. Severe is used t describe the intensity a
specic event (as in mild, mderate r severe). Te event itsel, hwever, may be relatively
minr medical signicance. (Fr example, ever is a cmmn relatively minr medical event,
but accrding t its severity it can be graded as mild ever r mderate ever. Anaphylaxis
is always a serius event and lie-threatening.) able 3 details the rare vaccine reactins;
case denitins are in Annex B. Mst the rare and mre serius vaccine reactins (e.g.
seizures, thrmbcytpenia, HHEs, persistent incnslable screaming) d nt lead t lng-
term prblems. Anaphylaxis, while ptentially atal, is treatable withut leaving any lng-
term eects. Althugh encephalpathy is included as a rare reactin t measles r DP
vaccine, it is nt certain that these vaccines in act cause encephalpathy.
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13Adverse events following immunization
Table 3: Rare vaccine reactions, onset interval and rates
Vaccine ReactionOnset
interval
Rate /
doses
BCG Suppurative lymphadenitis 26 mnths 110/104
BCG steitis 112 mnths 1700/106
Disseminated BCG inectin 112 mnths 0.191.56/106
Hib Nne
Hepatitis B Anaphylaxis 01 hur 1.1/106
Infuenza
(inactivated)
Anaphylaxis
Guillain-Barr syndrme (GBS)
Ocul-respiratry syndrme
0.7/106
12/106
76/106
Infuenza (live-
attenuated)
Anaphylaxis
Wheezing (children 611 mnths age)
- 2/106
14/100
Japanese
encephalitis
(inactivated)
Neurlgic events (encephalitis,
encephalpathy, peripheral neurpathy)
- 1-2.3/106
Measles/MMR/
MR*Febrile seizures 612 days 3/103
Trmbcytpaenia 1535 days 3/104
Anaphylaxis 01 hur ~1/106
Encephalpathy 612 days < 1/106
Oral plimyelitis VAPP 430 days 24 /106
Pertussis (DwP) Persistent (>3 hurs) incnslable screaming 024 hurs
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Immunization Safety Surveillance1414
Ke
ypoint
Comparing the observed rate of an adverse event in a single population
with the expected rate of this event for the vaccine used can help
identify if an event is related to the immunization or not. WHO has
developed vaccine-specic information sheets on observed ratesof vaccine reactions that provide observed reaction rates found in
literature.
(http://www.wh.int/vaccine_saety/initiative/tls/vaccinsheets/en/index.html)
Prevention and treatment of vaccine reactions
Vaccines are very rarely cntraindicated. Hwever, it is imprtant t check r
cntraindicatins t avid serius reactins. Fr example, vaccines are cntraindicated i
there is a pssibility serius allergy t a vaccine r its cmpnents. Live vaccines should
not be given to immunedecient children.
Advice n managing the cmmn reactins shuld be given t parents, in additin t
instructins t return i there are mre serius symptms. Such actin will help t reassure
parents abut immunizatin and prepare them r cmmn reactins.
Paracetaml, at a dse up t 15mg/kg every six t eight hurs with a maximum ur
dses in 24 hurs, is useul r the cmmn minr reactins. It eases pain and reduces ever.
Hwever, it is imprtant t advise nt t veruse Paracetaml as verdsing may harm the
vaccinee. A everish child can be cled with a tepid spnge r bath, and by wearing cl
clthing. Extra fuids need t be given t everish children. Fr a lcal reactin, a cld clth
applied t the site may ease the pain.
Practising lcal remedies r any serius vaccine reactin can risk the health and lie
vaccinee and are strngly discuraged. Early medical care by a qualied clinician will
minimize any unwanted utcme and ensure early recvery and may als save lie.
It is recmmended that acilities be available at all clinic setting t prvide initial emergency
care. All immunizatin prviders need t have skill and cmpetence n managing
anaphylaxis. Availability adrenalin and ther basic items in emergency tray is vital. (Mre
details n treatment vaccine reactins are in Annex B and r anaphylaxis in Annex C.)
Immunization errorrelated reactions
Immunizatin as used here means the usage a vaccine r the purpse immunizing
individuals. Usage includes all prcesses that ccur aer a vaccine prduct has le the
manuacturing/ packaging site, i.e. handling, prescribing and administratin the vaccine.
Note: Tis AEFI type was earlier categorized as Programme error (able 1)
Immunizatin errrs-related reactins are preventable and they derail the benet the
immunizatin prgramme (able 4). Te identicatin and crrectin these errrs in a
timely manner are, therere, great imprtance.
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15Adverse events following immunization
An immunizatin errr-related reactin may lead t a cluster events assciated
with immunizatin. Tese clusters are usually assciated with a particular prvider, r
health acility, r even a single vial vaccine that has been inapprpriately prepared r
cntaminated. Immunizatin errrs-related reactins can als aect many vials. Fr
example, reezing vaccine during transprt may lead t an increase in lcal reactins.
Table 4: Immunization error-related reactions
Immunization error Related reaction
Errr in vaccine
handling
Expsure t excess heat
r cld as a result
inapprpriate transprt,
strage r handling the
vaccine (and its diluent)
where applicable.
Use a prduct aer the
expiry date.
Systemic r lcal reactins due t
changes in the physical nature
the vaccine such as agglutinatin
aluminium-based excipients in reeze-
sensitive vaccines.
Failure t vaccinate as a result
lss ptency r nn-viability an
attenuated prduct.
Errr in vaccine
prescribing r
nn-adherence t
recmmendatins
r use
Failure t adhere t a
cntraindicatin.
Failure t adhere t vaccine
indicatins r prescriptin
(dse r schedule).
Anaphylaxis, disseminated inectin
with an attenuated live, VAPP.
Systemic and/r lcal reactins,
neurlgic, muscular, vascular r bny
injury due t incrrect injectin site,
equipment r technique.
Errr inadministratin
Use an incrrect diluentr injectin a prduct
ther than the intended
vaccine.
Incrrect sterile technique
r inapprpriate prcedure
with a multidse vial.
Failure t vaccinate due t incrrectdiluent , Reactin due t the
inherent prperties whatever was
administered ther than the intended
vaccine r diluent.
Inectin at the site injectin/
beynd the site injectin.
In the past, the mst cmmn immunizatin errr was an inectin (including bldbrne
virus) as a result nn-sterile injectin. Te inectin culd maniest as a lcal reactin (e.g.
suppuratin, abscess), systemic eect (e.g. sepsis r txic shck syndrme), r bldbrnevirus inectin (e.g. HIV, hepatitis B r hepatitis C). Hwever, with the intrductin
aut disabled (AD) syringes, inectin ccurrence has reduced signicantly. Still, inectin
can ccur in cases mass vaccinatin r disaster situatins, particularly i there is any
shrtage r prblems with lgistics and supplies. Tis can be avided by prper planning
and preparedness prgramme managers.
Te symptms arising rm an immunizatin errr may help t identiy the likely cause.
Fr example, children immunized with cntaminated vaccine (usually the bacterium
Staphylcccus aureus) becme sick within a ew hurs; lcal tenderness and tissue
inltratin, vmiting, diarrhea, cyansis and a high temperature are the mst requentsymptms. Bacterilgical examinatin the vial, i still available, can cnrm the surce
the inectin.
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Immunization Safety Surveillance1616
Sterile abscesses are rare (~1 per 100 000 dses) lcal reactins rm aluminium cntaining
vaccines, especially DP. Inadequate shaking the vaccine bere use, supercial
injectin, and use rzen vaccine increase the risk sterile abscess and lcal reactins.
Cntaminatin vaccine r injectin equipment can als lead t a bacterial abscess. Fr
BCG vaccine, injectin abscess can arise rm imprper injectin (subcutaneus rather
than intradermal injectin).
Ignring cntraindicatin can lead t serius vaccine reactins and it is cnsidered an
immunizatin errr. Immunizatin team shuld be clearly aware abslute and temprary
cntraindicatins. Any uncertainty shuld call r a reerral r cnsultancy rm a higher
level prgramme manager r paediatrician r physician. Hwever, it is equally imprtant nt
t verreact t cncerns alse cntraindicatins, which may lead t missed pprtunity
vaccinatin, reduce cverage and, thereby, increase the risk disease bth individuals
and the cmmunity.
Als, health-care wrkers need t have a clear understanding cntraindicatins and
precautins. Precautins are nt cntraindicatins, but decisin n vaccinatin requires a
case-based assessment. Use vaccines in pregnancy is limited r mstly nt recmmended.
Te vaccines which are recmmended in pregnancy wuld benet and prtect bth mther
and the newbrn. Hwever, the limited use vaccine in pregnancy is largely due t the
ptential risk and harm t the etus. Te presumed risk is mstly theretical and limited t
LAV which have demnstrated evidence ptential risk and harm, particularly in animal
mdels. Vaccine manuacturers instruct pregnancy as a cntraindicatin nt due t prven
evidence, but as a precautinary measure against litigatin.
avid immunizatin errr:
Vaccinesmustonlybereconstitutedwiththediluentsuppliedbythemanufacturer.
Reconstitutedvaccineshouldnotbeusedformorethansixhoursaer
recnstitutin and must be discarded at the end each immunizatin sessin and
never retained.
Nootherdrugsorsubstancesshouldbestoredintherefrigeratorofthe
immunizatin centre.
Immunizationworkersmustbeadequatelytrainedandcloselysupervisedtoensure
that prper prcedures are being llwed.
CarefulepidemiologicalinvestigationofanAEFIisneededtopinpointthecauseand t crrect immunizatin practices.
Adequateattentionmustbegiventopossibilityofcontraindications.
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17Adverse events following immunization
Case
studies
In 1992, one hospital in country A, ve neonates collapsed a few
minutes following immunization with BCG. Four were resuscitated
and one died. Muscle relaxant drugs were found in the refrigerator in
which vaccines were also kept.
Cause: Immunization error- related reaction. Use of muscle relaxant
instead of diluents.
In 20082009, in country B, during a school-based rubella
immunization programme, two 14 year-old girls collapsed within a
few minutes following immunization. The incidents occurred in two
separate places and at dierent times. Both girls were hospitalized
and later died.
Investigation revealed that both had informed the immunization
teams about past history of allergic reactions to some food products.
Also there were no emergency kits to manage anaphylaxis.
Causes: Immunization error-related reaction. Lack of attention on
possible contraindication and precautions to manage anaphylaxis.
Vaccine product-related reaction: Anaphylaxis is a known vaccine
reaction to rubella vaccine.
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 DTP vaccine.
Cause: Immunization error related reaction: Use of insulin instead of
DTP.
Immunization anxiety-related reactions
Individuals and grups can react in anticipatin t and as a result an injectin any
kind. Tis reactin is unrelated t the cntent the vaccine. Fainting is relatively cmmn,
but usually nly aects children aged ver ve years. Fainting des nt require any
management beynd placing the patient in a recumbent psitin. Te likelihd aints
can be anticipated when immunizing lder children, and reduced by minimizing stress in
thse awaiting injectin, thrugh shrt waiting times, cmrtable rm temperatures,
preparatin vaccine ut recipients view, and privacy during the prcedure.
Hyperventilatin as a result anxiety abut the immunizatin leads t specic symptms
(light-headedness, dizziness, tingling arund the muth and in the hands). Tis is als
cmmn in mass vaccinatin campaigns.
Yunger children tend t react in a dierent way, with vmiting a cmmn anxiety symptm.
Breath-hlding may ccur, which can end in a brie perid uncnsciusness, during
which breathing resumes. Tey may als scream t prevent the injectin r run away.
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Immunization Safety Surveillance1818
An anxiety reactin t injectin can include cnvulsins in sme case. Tese children d
nt need t be investigated but shuld be reassured.
Tese reactins are nt related t the vaccine, but t the injectin. Sme individuals may be
needle-phbic, aggravating such reactins. In a grup situatin, mass hysteria is pssible,especially i a vaccinee is seen t aint r have sme ther reactin. Clear explanatins abut
the immunizatin and calm, cndent delivery will decrease the level anxiety abut the
injectins, and thus reduce the likelihd an ccurrence.
It is imprtant t nte that aintish attack (syncpe) can be misdiagnsed as anaphylaxis.
Health wrkers need t dierentiate between the tw statuses. (Details are given in Annex
B.) Very careul bservatin and clinical judgement is necessary. Hwever, by mistake, a
health- care wrker may administer a single dse adrenaline (intramuscularly) t a
vaccinee with just syncpe, but it des nt harm the vaccinee. avid such unnecessary
medical emergency interventins, cntinued training and awareness r health sta is
necessary.
Casestudies
In 2004, a mass school-based measles-rubella immunization
campaign was conducted among 1219 years in country D. On the
rst day, 44 children were hospitalized with either hyperventilation
or/and vomiting. Investigation concluded that more than 90% were
anxiety reactions, and except for two cases all were discharged from
hospital the same day.
Cause: Immunization anxiety-related reactions
Coincidental events
An event may ccur cincidentally with immunizatin and at times may be alsely
attributed t be a result the vaccine. In ther wrds, a chance tempral assciatin (i.e.
event happening aer immunizatin) is alsely cnsidered t be caused by immunizatin.
Tese purely tempral assciatins are inevitable given the large number vaccine dses
administered, especially in a mass campaign.
Vaccines are nrmally scheduled early in lie when inectins and ther illnesses arecmmn, including maniestatins an underlying cngenital r neurlgical cnditin.
It is, therere, pssible t encunter many events, including deaths, t be alsely attributed
t vaccine thrugh chance assciatin.
Fr example, sudden inant death syndrme (SIDS r ct death) incidence peaks
arund the age early childhd immunizatin. S, many SIDS cases will be in
children wh have been recently immunized. Hwever, cntrlled studies have shwn
that the assciatin SIDS and immunizatin is purely cincidental, nt causal
(Hwsn et al, 1991).
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19Adverse events following immunization
Case
studies
In response to a severe diphtheria outbreak in country E in 1996, DT
was delivered to children in a mass campaign. The death of a seven
year-old girl, two to three days following immunization, was reported.
The symptoms reported included convulsions that might have beenattributable to a vaccine reaction. Upon investigation, it was found
that the girl had a history of convulsions and neurological symptoms
unrelated to immunization.
Cause: Coincidental event
In 2010, six infants died within 48 hours following administration
of pentavalent (DTP-HepB-Hib) vaccine in country F. Use of
vaccine was temporarily suspended. A high-level investigation was
warranted, as the deaths had led to a public concern, and health
sta were reluctant to use the vaccine.
Cause: Coincidental. Out of six cases, three were conrmed
coincidental. One was suocation and two were due to underlying
infections. Among the other three, one was anaphylactic and the
other two remained undetermined.
In 2010, the death of a four-month old infant following DTwP was
reported in country G. Within a week, six more cases of severe local
reactions were reported with the same batch of DTwP, causing a high
public and media attention. Implicated vaccine lot was temporarily
suspended and replaced with another lot, and a comprehensive
investigation was done including toxicity and sterility testing at
national and a WHO-accredited and national laboratories.
Cause: Coincidental. Causality assessment conrmed the death as
coincidental, but six reported severe local reactions were most likely
due to the immunization errors-related reactions.
Cincidental adverse events may be predictable. Te number events t be expected
depends upn the size the ppulatin and the incidence disease r death in the
cmmunity. Knwledge these backgrund rates disease and deaths, particularly agespecic disease incidence rates, allws estimatin the expected numbers cincidental
events.
Fr example, let us assume that ne millin children aged 115 years are immunized in
a mass campaign and the backgrund age specic mrtality rate r this ppulatin is 3
per 1000 per year. Ten, 250 deaths can be expected in the mnth aer immunizatin and
eight deaths n the day the immunizatin, simply by cincidence. Tese deaths will be
temprally assciated with, even thugh entirely unrelated t, immunizatin.
A similar calculatin is shwn in able 5 r inant (aged under ne-year) deaths in selected
Western Pacic Reginal cuntries r the number deaths temprally assciated withrutine DP immunizatin. Tere will be many cincidental deaths in the day, week and
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Immunization Safety Surveillance2020
mnth aer immunizatin, which are nly temprally related t immunizatin. Te actual
number cincidental deaths depends n the ppulatin size, inant mrtality rate, the
number immunizatin episdes, and the immunizatin cverage.
When cmparing expected versus actual events, it is pssible t use statistical analysis tensure that dierences are nt simply the result chance. It is imprtant t als nte that
the expected number death calculatins presented belw may be infated as it is assumed
that children wh are near t death will still be immunized.
Table 5: Estimated coincidental deaths temporally linked to DPT
immunization in selected countries in the Western Pacic Region
Country
Infantmortalityrate per
1000 livebirths (IMR)
Number ofbirths per
year
Estimated number of infant deathduring year in
Month afterimmunization
Week afterimmunization
Day afterimmunization
=(IMR*N/12)*nv*ppv
=(IMR*N/52)*nv*ppv
=(IMR*N/365)*nv*ppv
Australia 5 267 000 300 69 10
Cambdia 69 361 000 5605 1293 185
China 18 18 134 000 73 443 16 948 2421
Japan 3 1 034 000 698 161 23
Te La Peples
Demcratic
Republic
48 170 000 1836 424 61
New Zealand 5 58 000 65 15 2
Te Philippines 26 2 236 000 13 081 3019 431
Nte: Assumes unirm distributin deaths and children wh are near t death will stil l be immunized.
Inant mrtality and births rm 2008 immunizatin summary, WHO/UNICEF (2010).
IMR= Inant mrtality rate per 1000 live birth; IMR/1000
nv = number immunizatin dses: assumed here t be three dse schedule; 3.
ppv = prprtin ppulatin vaccinated: assumed here t be 90% r each dse; 0.9.
In general, cincidental events are clearly unrelated and may nt require any investigatin
(e.g. pneumnia). Hwever, certain serius events may be blamed n the vaccine by the
parents r public r media because the clse tempral assciatin with immunizatin,especially i the child was previusly healthy. Such cases need t be investigated, t allay
public ear and maintain credibility. Respnding t public cncerns abut immunizatin
saety is imprtant in maintaining cndence in the immunizatin prgramme. Availability
inrmatin n backgrund rates reprted cincidental event may be helpul in the
investigatin an AEFI.
I the same r similar events als aected thers in the same age grup arund the same
time but wh did nt receive the suspect vaccine(s), then a cincidental event is mre likely.
Tere may als be evidence shwing that the event is nt related t immunizatin.
With increasing awareness AEFI surveillance even health sta may reprt mrecincidental events. Als, with intrductin a new vaccine, there is a trend reprting
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21Adverse events following immunization
many AEFIs, including cincidental events. It is crucial t dierentiate these reprted
cincidental events rm ptential signals.
Summary Adverse events may occur due to some inherent properties of the
vaccine (vaccine product-related reaction) or due to quality defect
(vaccine quality defect-related reaction) or due to immunization
errors-related reactions. At times, the event may be unrelated to
immunization, but may have a temporal association (coincidental
event).
Immunization anxiety-related reactions are common, resulting from
fear or pain of injection rather than the vaccine. In some cases, the
cause of the AEFI remains unknown.
Antigen/vaccine-specic background rates of vaccine reaction
are useful to guide decision-making on vaccine related reactions.
Minor vaccine reactions are common and do not require special
treatments. Rare, serious vaccine reactions need a timely treatment
by qualied medical personnel.
Immunization error-related reactions (previously classied as
programme errors) are avoidable.
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Immunization Safety Surveillance22
Establishing immunizationsafety surveillance
Pharmacvigilance is the practice detecting, assessing, understanding, respnding
and preventing adverse drug reactins, including reactins t vaccines. It is nw
an integral part the regulatin drug and vaccine saety. While vaccines are
cnsidered drugs, they are dierent and require mdied systems t mnitr adverse
events. Immunizatin saety is the prcess ensuring and mnitring saety all aspects
immunizatin, including vaccine quality, adverse events, vaccine strage and handling,
vaccine administratin, dispsal sharps and management waste.Immunizatin saety surveillance systems exist at natinal and internatinal levels t
ensure eective mnitring and prmpt actins in respnse t AEFIs. Immunizatin saety
surveillance needs t be a cllabrative venture between the immunizatin prgramme
and, when it exists, the NRA, as bth parties are respnsible r the saety vaccines.
Depending n the cuntry administrative and peratinal structure, ne unit/institutin
needs t be the cal pint r immunizatin saety surveillance. Tis can even be delegated
t anther rganizatin (e.g. a university department), as lng as the links with the NRA
and the natinal immunizatin prgramme are maintained. Te system shuld build n
and mutually strengthen any existing system reprting inrmatin (e.g. immunizatin
cverage reprts, disease incidence reprts, and adverse drug reactin reprts). Tebest reprting system is the ne which achieves the highest cmpliance and takes timely
apprpriate actin in respnse t reprts.
Objectives
Tere are several ptential bjectives r establishing immunizatin saety surveillance.
Clariying the mst imprtant bjective(s) the system will assist in design and
implementatin. Te relative imprtance the bjectives will depend n the state the
immunizatin prgramme and lcal circumstances. Te bjectives may als change ver
time.
Te majr gal immunizatin saety surveillance is early detectin and apprpriate and
quick respnse t adverse events in rder t lessen the negative impact n the health the
individuals and n the immunizatin prgramme. It is an indicatr prgramme quality.
It will als enhance prgramme credibility and prvide actual cuntry and reginal data n
vaccine saety.
In establishing immunizatin saety surveillance, the bjectives, clearly articulated, shuld
engender the supprt health wrkers t encurage reprting. I resurces are limited,
priritizing the bjectives is recmmended. One ptin is t have a minimum level
surveillance cnducted n the natinal level t detect immunizatin errrs with a ewhspitals/acilities cnducting enhanced AEFI surveillance.
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Establishing immunization safety surveillance 23
It is imprtant r any inrmatin btained thrugh immunizatin saety surveillance t
be immediately assessed and analysed t identiy and respnd t prblems. Respnse is a
critical aspect immunizatin saety surveillance.
Specic objectives of the immunization safety surveillance:
To detect and timely identify problems with vaccines, which could be due to the
inherent properties or quality defects of vaccines.
To detect, correct and prevent immunization errors-related reactions (previously
classied as programme errors).
To estimate expected vaccine reaction rates (background rates) in the
population (by country, by region and globally).
To identify clustering or unusually high rates of AEFI even if they are consideredmild.
To ensure that coincidental events do not negatively aect the immunization
programme.
To ensure and facilitate causality assessment of coincidental, serious and
unexpected/unusual AEFIs.
To identify signals of unknown vaccine reactions, generate new hypotheses
about vaccine reactions that are specic to a given population.
To maintain the condence of the community and health sta in theimmunization programme by appropriately and timely responding to their
concerns about immunization safety.
To eectively communicate with parents, community, the media and other stake
holders to create awareness on AEFIs without jeopardizing the immunization
programme.
To collaborate and share information with the WHO Regional Oce for the
Western Pacic and globally (through post-marketing surveillance/PMS
Network), in order to generate new and additional information on vaccine safety.
Steps for establishing a system
When develping an immunizatin saety surveillance system, cuntries are advised t
cnsider the llwing steps:
1. Clariy and agree n rles and respnsibilities bth the immunizatin prgramme
and NRA in immunizatin saety surveillance. It is imprtant t designate a
surveillance implementatin bdy.
2. Develp a prtcl with clearly-dened bjectives the immunizatin saety
surveillance: identied strategies, activities t be dne, and availability resurces.
3. Clearly identiy the rle and respnsibilities each sta categry invlved in
immunizatin saety surveillance.
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Immunization Safety Surveillance2424
4. Seek legal prvisin r vaccine pharmacvigilance and endrsed gvernment
cmmitment.
5. Establish a natinal (central) expert cmmittee r causality assessment and r
highest technical supprt and decisin-making. Large cuntries may have state/
prvince/reginal experts cmmittees r similar purpses and smaller cuntries,
where such experts are nt available, can identiy a supprting unit rm the regin.
6. Develp and disseminate a list events t be reprted (and investigated) and
their case denitins, standard investigatin prcedures, and AEFI reprting and
investigatin rms. (Fr mre inrmatin, visit: www.wh.int/entity/vaccine_
saety.)
7. rain sta n reprting, data analysis, and investigatin and reprt preparatin,
depending n at what level each unctin has t be dne. Develp training materials
and training mdules suitable r the cuntry.
8. Make sure the sta are aware that mnitring and evaluatin activities areimprtant and necessary.
9. Develp a cmmunicatin plan t address issues and inrmatin based n
immunizatin and saety surveillance.
10. Cnsider establishment a legal ramewrk and a cmpensatin scheme where
applicable. Identiy als i the legal ramewrk is a gvernment plicy.
Role and responsibility of NRA in immunization safety
surveillance
NRAs are respnsible r ensuring that every pharmaceutical prduct - including a vaccine- used within the cuntry is (i) gd quality, (ii) eective, and (iii) sae r the purpse
r purpses r which it is prpsed. Whereas the rst tw criteria must be met bere any
apprval the vaccines medical use, the issue saety is mre challenging. Strengthening
NRA activities leads t ensure vaccine saety. Te Glbal Vaccine Saety Initiative (GVSI),
thrugh the WHO-led Vaccine Saety Blueprint Prject, has already develped strategies t
strengthen NRAs, particularly in lw- and lw-middle incme- cuntries.
Te immunizatin prgramme and NRA cllectively play specic rles and respnsibilities
in immunizatin saety surveillance. WHO cnsiders that in all vaccine-prducing cuntries
and in all ther cuntries where an NRA exists, the NRA must be invlved in immunizatin
saety surveillance. WHO has dened six unctins t be carried ut by NRA, as llws:
1. marketing authrizatin and licensing activities: with clear written instructin r
licensing prducts and manuacturers;
2. pharmacvigilance, including surveillance AEFI;
3. NRA lt release: system r lt release;
4. labratry access: use labratry when needed;
5. regulatry inspectin: regular inspectin manuacturers r GMP cmpliance;
and
6. regulatry versight clinical trials: evaluatin clinical perrmances thrughauthrized clinical trials.
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25Establishing immunization safety surveillance
WHO carries ut peridical assessment unctins NRA in all cuntries, leading t
strengthened NRA unctins. A WHO manual r assessment the natinal regulatry
systems r vaccines was published in_2009 (http://www.wh.int/immunizatin/tpics/
nra_aidememire_2003.pd). Tis assessment is carried ut using a tl specically
designed t assess regulatry systems and the abve six unctins. Perrmance indicatrs
and sub-indicatrs have been develped r each unctin. Sme indicatrs and sub-
indicatrs are marked as critical, i.e. mandatry t pass t qualiy NRA as ully unctining.
Fr pharmacvigilance surveillance AEFI, there are seven indicatrs and which six
are critical (Annex E). Out the six unctins, rst tw are mandatry r all cuntries
t perrm, irrespective their status as vaccine-prducing r nt. Furthermre, WHO
recmmends that all cuntries which d nt actually prduce vaccines must still dene
minimum specicatins r the vaccines they use. Tere shuld als be a system pst-
marketing surveillance t detect i there are prblems vaccine perrmance in the eld.
Certain adverse events llwing vaccinatin shuld be mnitred, investigated, and
reprted.
Te NRA may have limited knwledge abut the immunizatin prgramme. It is, therere,
essential that the immunizatin prgramme manager be invlved in immunizatin saety
surveillance. Te respective rle the tw key parties needs t be established.
Role and responsibility of immunization programme
(manager) in immunization safety surveillance
An eective immunizatin saety surveillance system is required invlving health wrkers
at all levels in the immunizatin prgramme. Tis sectin identies the key rle players atdierent levels the surveillance system and als utlines their rles and respnsibilities in
carrying ut surveillance activities. Hwever, their rles and respnsibilities will depend n
the peratinal levels in dierent cuntry settings.
It is assumed that a cuntry shuld have three levels immunizatin saety surveillance:
natinal (central), intermediate (state/prvince/regin/district) and service-prvider level.
In small Pacic islands, hwever, the surveillance may be limited t nly tw levels. When
a cuntry has three levels, unctins and respnsibilities amng intermediate and natinal
levels are shared by varying degrees, depending n cuntry size and the health-care system.
Immunization service provider level
In these guidelines, immunizatin service prvider level reers t the lwest administrative
level in the cuntry, which prvides the immunizatin service t the public. Amng the
tasks immunizatin service prviders are the llwing:
Detection o AEFIs
Inquiries shuld be made at the clinic, hspital r in cmmunity, individually
regarding any AEFIs experienced aer previus vaccinatin rm the recipient r
parent/guardian the recipient.
I treatment is necessary r a particular cnditin, the recipient having AEFIs
shuld be reerred t the nearest hspital/health acility.
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Immunization Safety Surveillance2626
Recording o AEFI
Supply necessary rms and registers r immunizatin saety surveillance shuld
be maintained. All necessary data shuld be entered int the rms/recrds/registers.
Reporting o AEFITe higher-up administrative/peratinal level shuld be immediately inrmed
all serius events, unusual AEFIs, and deaths.
Other cases shuld be reprted in a rutine way, as instructed by the next
administrative/peratinal level.
Investigation o AEFI
I the capacity t carry ut an investigatin exists, it may be dne at this level. All
investigatins required amng reprted AEFIs, as listed in the natinal guidelines,
need t be dne at the earliest pssible time. Cmmunicatin with the sta and
the cmmunity is essential. Public shuld be kept inrmed regarding what is
being dne during the investigatin and, nce it is ver, the cnclusins and results
shuld be shared with ther members the team and the cmmunity. Findings
investigatin shuld be disseminative with bth service prvider and next
administrative / peratinal level authrity. I the guidelines instruct, investigatin
reprts need t be submitted t the next administrative/peratinal level r natinal
level authrity.
Correctiveaction
Crrective actin, particularly related t immunizatin errrs, shuld be taken
immediately. It shuld be based n the ndings investigatin.
Analysis o AEFIIt is recmmended t keep bth line listing and detail inrmatin separately.
Depending n the capacity sta attached at this level, analysis may be limited t
the basic variables.
Public education/communication
Whenever an pprtunity is available, the public shuld be cmmunicated with and
be made aware what is being dne. Peple shuld be educated regarding AEFIs.
Intermediate level
Te use the term intermediate level in these guidelines will be varied, depending n
the cuntries health-care service administratin structures. It may reer t ne r mre
administrative levels in a cuntry. Hence, intermediate level represents all levels between
the natinal and lwest administrative levels in a specic cuntry.
(Fr example, cuntry A may have an administrative structure n ur levels: natinal,
prvincial, district and divisinal. Te prvincial and district levels cnstitute the
intermediate level r the cuntry.)
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27Establishing immunization safety surveillance
ReportingofAEFI
Te natinal level shuld be inrmed immediately serius events, unusual AEFIs
and deaths. Other cases shuld be reprted rutinely, as stipulated by natinal level
authrity. All recrds n AEFI surveillance shuld be maintained.
Investigation o AEFI
All investigatins required amng reprted AEFIs, as listed in natinal guidelines,
need t be dne at the earliest pssible time. In mst settings, capacity t cnduct a
cmprehensive investigatin at immunizatin service prvider level des nt exist.
Terere, cllectin preliminary inrmatin detailed investigatins is en
the respnsibility at this level. Develping capacity t carry ut such investigatin is
necessary and lgical. Findings investigatin shuld be disseminative with bth
service prvider and natinal level authrities.
Corrective action
Crrective actin shuld be taken immediately. It shuld be based n the ndings investigatin. In practice, intermediate level has mre respnsibilities t
implement crrective actins bth lgistically and administratively. Fr example, i
any immunizatin errr-related reactins are bserved, strengthening supprtive
supervisin, training and even lgistic replacements culd be implemented by the
authrities at this level.
Analysis o AEFI
Carrying ut data analysis is necessary. Reprts need t be prduced based n
ndings data analyses and investigatins.
Monitoring and supervision/trainingMnitring, supervisin and training are key unctins at this level. Authrities
need t develp the capacity at this level t carry ut these unctins eciently and
eectively. Whenever necessary, the natinal level can assist intermediate level r
these activities, including prviding standard rmats r supprtive supervisin,
guidelines and training materials.
National level
InvestigationandcausalityassessmentofAEFI
Investigatins that need natinal level experts service (e.g. serius cases, deaths,
AEFIs with public cncerns) need t be dne at the earliest pssible time. Causalityassessment by natinal expert cmmittee needs t be acilitated. I necessary, urther
research needs t be cnducted t test a hypthesis generated by the surveillance
system/investigatin.
Corrective action
Crrective actin shuld be taken immediately. It shuld be based n the ndings
investigatin. Vaccine withdrawal r suspensin shuld be taken nly i available
data are strngly supprted by the causative link the vaccines. Crrective actin
even can lead t plicy r/and prgramme strategy changes.
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Immunization Safety Surveillance2828
Analysis and sharing o AEFI data
Reprts shuld be prduced n ndings data analyses and investigatins.
AEFI data need t be shared amng all stakehlders respnsible r cuntry EPI,
immunizatin prgramme managers, NRA, NCL, academia and, when necessary,
manuacturers. Cuntries are encuraged t share data reginally and glbally
thrugh the WHO Prgramme r Internatinal Drug Mnitring t generate
additinal and new inrmatin n vaccine saety.
Publiceducation/communication
Whenever needs arise, cnducting public and media awareness is necessary.
Develping cmmunicatin plan is als essential.
Monitoringandsupervision/training
Mnitring and supervisin immunizatin service is necessary. Guidance and
adequate training shuld be prvided t the sta n AEFI surveillance and gd
quality immunizatin practices. Whenever necessary, the sta must be re-trained.Develping training materials and getting WHO supprt, i necessary, shuld be
dne.
Table 6: Programme implementation level, responsibility
and purpose of surveillance
Programme
implementation
level
Responsibility Related reaction
Lcal level
(Immunizatin
prvisin level)
DetectionofAEFIs
ReportingofAEFIs
Maintainingofrecords/
registers
Preliminary
investigatins
Basicanalysisofdata
Carryingoutcorrective
actins
Communicationwith
patients and cmmunity
Casedetectionandreportingaretherstand
unding steps surveillance.
Establishingagoodlinkwithprivatesector
will enhance private sectr reprting as well.
Conductingbasicanalysisofdata&
preliminary investigatin will help t
identiy crrective actins, particularly
immunizatin errrs, in a timely manner at
lcal level and d the needul crrectins.
Goodcommunicationatlocallevelisvery
imprtant as it will lead t limit rumurs
and negative messages again timely in lcalsettings. Natinal level media get mst
negative inrmatin rm lcal reprters.
Hence, necessity gd cmmunicatin at
the lcal level is urther justiable.
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29Establishing immunization safety surveillance
Programme
implementation
level
Responsibility Related reaction
Intermediate level
(Reginal/
prvince/
district/
twn etc.,)
Verifyingreportingdata Lookingforadditional
data (e.g. clusters)
Conducting
investigatins
(and supprting
investigatins t bth
lcal and natinal
teams)
Analysisofdata
Feedback(investigationand data analysis)
Guidingandmonitoring
t carry ut crrective
actins
Supportivesupervision
n surveillance activities
at lcal level
Training
Communicationwith
stakehlders
Vericationofdatawillensurethequalityofdata.
Veryoenclustersandvaccine-related
prblems are identied at this level.
Conductinginvestigationbyintermediate
level will assure quality (availability
resurces including experts) and
independence investigatin.
Atintermediatelevel,theamountofdata
is very en sucient t carry ut detailed
analysis t identiy cause-specic AEFIs.
Findings are necessarily needed t be
shared with lcal level, in rder t carry
ut necessary crrective actins in a timely
manner. Als guidance and ther lgistical
supprt need t be prvided t the lcal level.
Supportivesupervisionandtrainingwill
lead t ensure smth unctining AEFIs
surveillance.
Communicationwithstakeholders,including
media, is imprtant t avid a natinal level
crisis AEFIs and build cndence nimmunizatin prgramme.
Natinal level Conducting
investigatins
(and supprting
investigatins belw
levels)
Causalityassessment
and research
Dataanalysis/feedback
Guidanceand
mnitring t carry ut
crrective actins
Supportivesupervision
n surveillance activities
Training
Communicationwith
stakehlders
Sharinginformation
with internatinal
agencies (WHO,
UNICEF) and
manuacturers
Conductingdetailedinvestigationsand
causality assessment n cases with natinal
interest.
Dataanalysisislargelyfocussedon
identiying vaccine-related issues, as it will
lead t peratinal and plicy decisins n
vaccine prcurement and management. It
als has an impact at the internati