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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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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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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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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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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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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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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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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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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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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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.


30/112


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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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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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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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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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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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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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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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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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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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

immunization safety surveillance

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