INTRODUCTION OF ROTAVIRUS VACCINES

Transcription

1 WHO/IVB/13.08 INTRODUCTION OF ROTAVIRUS VACCINES Infrmatin fr Plicy Makers, Prgramme Managers, and Health Wrkers WHO Geneva, July 31, 2013

2 The Department f Immunizatin, Vaccines and Bilgicals thanks the dnrs whse unspecified financial supprt has made the prductin f this dcument pssible. This dcument was published by the Expanded Prgramme n Immunizatin f the Department f Immunizatin, Vaccines and Bilgicals Ordering cde: WHO/IVB/13.08 Published in Octber 2013 This publicatin is available n the Internet at: dcuments/ Cpies f this dcument as well as additinal materials n immunizatin, vaccines and bilgicals may be requested frm: Wrld Health Organizatin Department f Immunizatin, Vaccines and Bilgicals CH Geneva 27 Switzerland Fax: vaccines@wh.int Wrld Health Organizatin 2013 All rights reserved. Publicatins f the Wrld Health Organizatin can be btained frm WHO Press, Wrld Health Organizatin, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: ; fax: ; bkrders@wh.int). Requests fr permissin t reprduce r translate WHO publicatins whether fr sale r fr nncmmercial distributin shuld be addressed t WHO Press, at the abve address (fax: ; permissins@wh.int). The designatins emplyed and the presentatin f the material in this publicatin d nt imply the expressin f any pinin whatsever n the part f the Wrld Health Organizatin cncerning the legal status f any cuntry, territry, city r area r f its authrities, r cncerning the delimitatin f its frntiers r bundaries. Dtted lines n maps represent apprximate brder lines fr which there may nt yet be full agreement. The mentin f specific cmpanies r f certain manufacturers prducts des nt imply that they are endrsed r recmmended by the Wrld Health Organizatin in preference t thers f a similar nature that are nt mentined. Errrs and missins excepted, the names f prprietary prducts are distinguished by initial capital letters. All reasnable precautins have been taken by the Wrld Health Organizatin t verify the infrmatin cntained in this publicatin. Hwever, the published material is being distributed withut warranty f any kind, either expressed r implied. The respnsibility fr the interpretatin and use f the material lies with the reader. In n event shall the Wrld Health Organizatin be liable fr damages arising frm its use. The named authrs alne are respnsible fr the views expressed in this publicatin. Printed by the WHO Dcument Prductin Services, Geneva, Switzerland. 1 I ntrductin f Rtavirus vaccines

3 Cntents Intrductin... 3 Why this dcument?... 3 What is included in this dcument?... 3 An integrated apprach fr saving lives: The Prtect, Prevent and Treat framewrk fr pneumnia and diarrhea... 4 WHO recmmendatins fr rtavirus vaccines... 6 Overview f the planning prcess... 8 TEN KEY ELEMENTS OF A SUCCESSFULL NATIONAL PLAN FOR THE INTRODUCTION AND IMPACT EVALUATION OF ROTAVIRUS VACCINES Analyze the epidemilgy f rtavirus disease in yur cuntry r in similar settings Review the age at which children are receiving each dse f DTP/pentavalent vaccine (timeliness) and the cverage achieved Review immunizatin cverage at sub-natinal level and identify areas where cverage is lwer than natinal targets Select the vaccine and vaccinatin schedule that is mst suitable fr yur cuntry Assess the lgistic implicatins f yur vaccine and schedule selectin Review and discuss ther peratinal factrs that are relevant in yur cuntry Plan integrated actins fr the preventin and cntrl diarrhea (and pneumnia) Identify activities t establish/enhance rtavirus disease surveillance and t mnitr and evaluate the impact f rtavirus vaccine Prepare a plan t mnitr and investigate any adverse events fllwing immunizatin (AEFI) Prepare an intrductin plan at natinal level and facilitate the develpment f district and lcal level micr-plans fr rtavirus vaccine intrductin Annex 1: Dcumented reductins in pneumnia and diarrhea mrbidity and mrtality with selected interventins Annex 2: Overview f strage vlumes fr "traditinal" versus "rtavirus" vaccines Annex 3: Strage vlumes fr rtavirus vaccine prducts Annex 4: Sample AEFI reprting frm using cre variables Annex 5: Intussusceptin Annex 6: Key Advcacy & Cmmunicatins Messages Related t Rtavirus Vaccines Annex 7: Frequently Asked Questins fr Health Wrkers Annex 8: Rtavirus vaccines: A Pcket Guide fr Health Wrkers I ntrductin f Rtavirus vaccines

4 Intrductin Why this dcument? WHO recmmends that rtavirus vaccines be included in all natinal immunizatin prgrammes. Rtavirus vaccine shuld be cnsidered a pririty particularly in cuntries with high rtavirus gastrenteritis (RVGE) assciated fatality rates, such as in Suth and Suth- Eastern Asia, and sub-saharan Africa. T maximize the impact f rtavirus vaccine it is imprtant t develp a cmprehensive and realistic intrductin plan. What is included in this dcument? KEY MESSAGE The use f rtavirus vaccines shuld be part f a cmprehensive strategy t prevent diarrhea and pneumnia Glbally, pneumnia and diarrhea are amng the leading causes f child mrtality. Tgether pneumnia and diarrhea accunt fr 29% f deaths in children <5 years (an estimated 2 millin deaths/year). The slutins fr tackling pneumnia and diarrhea d nt require majr advances in technlgy. Children are dying because services are prvided piecemeal and thse mst at risk are nt being reached. This dcument includes: þ infrmatin and guidance t assist natinal managers t cnsider all the peratinal preparatins that shuld be included in a rtavirus vaccine intrductin plan, nce a decisin t intrduce the vaccine has been made; and þ key technical infrmatin and up-t date references t help prgramme managers and health wrkers t successfully incrprate rtavirus vaccine int the natinal immunizatin prgramme. Many f the causes and slutins fr childhd pneumnia and diarrhea are inter-related and need t be addressed tgether. The intrductin f rtavirus vaccine is an pprtunity t integrate and imprve the planning, delivery and mnitring f a cmprehensive package f health interventins fr pneumnia and diarrhea. Each cuntry shuld develp cuntry-specific plans n hw rtavirus vaccine can be intrduced in a manner that strengthens the existing natinal immunizatin prgramme and is part f an integrated strategy t preventing pneumnia and diarrhea child deaths. 3 I ntrductin f Rtavirus vaccines

5 An integrated apprach fr saving lives: The Prtect, Prevent and Treat framewrk fr pneumnia and diarrhea Amng partners, academics, NGOs, gvernments, cmmunities and health wrkers themselves, it is well recgnized that pneumnia and diarrhea are mst effectively addressed in a crdinated manner. They share the same determinants, and thus als share cntrl strategies, as well as delivery systems. Bth pneumnia and diarrhea are caused by multiple pathgens and n single interventin alne can manage t address either prblem. Mst f the required actins are cmmn t bth diseases. The gal t end childhd deaths due frm pneumnia and diarrhea by 2025 is the driving frce behind the WHO/UNICEF Integrated Glbal Actin Plan fr Pneumnia and Diarrhea (GAPPD) 1. The actin plan identifies pprtunities t better integrate activities as well as capture synergies and efficiencies. It envisins the varius interventins fr cntrlling pneumnia and diarrhea in children less than five years f age as: prtecting children by establishing and prmting gd health practices; preventing children frm becming ill frm pneumnia and diarrhea by ensuring universal cverage f immunizatin, HIV preventin and healthy envirnments; treating children wh are ill frm pneumnia and diarrhea with apprpriate treatment. Figure 1: Cmplementarity f pneumnia and diarrhea interventins Diarrhea Vitamin A suplementatin Vaccinatin : rtavirus Safe water & imprved sanitatin Lw-smlarity ORS, zinc & cntinued feeding Prtect Breastfeeding prmtin & supprt Prevent Measles Vaccinatin Treat Imprved care seeking behaviur and referral Adequate cmplementary feeding Handwashing with sap Imprved case management at cmmunity and health facility levels Preventin f HIV Cntinued feeding Pneumnia Vaccinatin (PCV, Hib, pertussis) Reduced husehld air pllutin Antibitics fr pneumnia Oxygen therapy (where indicated) 1 WHO/UNICEF Ending Preventable Child Deaths Frm Pneumnia and Diarrhea by 2025: The integrated Glbal Actin Plan fr Pneumnia and Diarrhea (GAPPD). Available frm (accessed July 25, 2013). 4 I ntrductin f Rtavirus vaccines

6 Over the past 20 years, research int specific pneumnia and diarrhea interventins has shwn that the fllwing interventins and activities wrk (see Annex 1 fr mre details): Exclusive breastfeeding fr 6 mnths and cntinued breastfeeding with apprpriate cmplementary feeding reduces the nset and severity f diarrhea and pneumnia. Preventive vitamin A supplementatin reduces all-cause mrtality and diarrhea-specific mrtality in children 6-59 mnths. Vaccinatin against Streptcccus pneumnia (Spn) (pneumcccal cnjugate vaccine PCV), Haemphilus influenza type b (Hib), rtavirus, measles and pertussis. Use f simple, standardized guidelines fr the identificatin and treatment f pneumnia and diarrhea in the cmmunity, at first-level health facilities and at referral hspitals, such as thse fr integrated management f childhd illness (IMCI), substantially reduces child deaths. Oral rehydratin slutin (ORS), especially the lw-smlarity frmula, and use f zinc supplements are prven, life-savers fr treatment f children with diarrhea. Innvative demand creatin activities are imprtant fr achieving behavir change and sustaining lng-term preventive practices. Water, sanitatin and hygiene interventins (WASH), including access t and use f safe drinking-water and sanitatin, as well as prmtin f key hygiene practices (e.g. handwashing with sap). Reductin f husehld air pllutin with imprved stves has been shwn t reduce severe pneumnia. Safer and mre efficient energy in the hme prevents burns, saves time and fuel csts, and cntributes t better develpment pprtunities. Althugh these interventins frm the cre f primary health care (PHC) in many places they are nt always prmted tgether t achieve maximum benefit. The prpsed interventins utlined in GAPPD are nt new, but implementing them t scale will require greater crdinatin and effrt. This verall apprach builds n and is linked t the achievement f the Millennium Develpment Gal t reduce child mrtality (MDG4), as well as t the successful implementatin f the UN Glbal Strategy fr Wmen s and Children s Health, including Every Wman, Every Child, the UN Cmmissin n Life-Saving Cmmdities, the Glbal Vaccine Actin Plan (GVAP) and the A Prmise Renewed cmmitment t child survival. 5 I ntrductin f Rtavirus vaccines

7 WHO recmmendatins fr rtavirus vaccines Rtavirus vaccines WHO psitin paper January WHO recmmends that rtavirus vaccines be included in all natinal immunizatin prgrammes and cnsidered a pririty particularly, in cuntries with high rtavirus gastrenteritis-assciated (RVGE) fatality rates, such as in suth and suth-eastern Asia and sub-saharan Africa. Recmmended vaccinatin schedule: Fllwing a review f new evidence n age-specific burden f rtavirus disease and deaths, timeliness f vaccinatin, and the safety and effectiveness f different immunizatin schedules, WHO recmmends that the first dse f rtavirus vaccine be administered as sn as pssible at r after 6 weeks f age, alng with diphtheria-tetanus-pertussis (DTP) r pentavalent vaccinatin, t ensure inductin f prtectin prir t natural rtavirus infectin: Rtarix (RV1) shuld be administered rally in a 2-dse schedule at the time f DTP/penta1 and DTP/penta2 cntacts, with an interval f at least 4 weeks between dses. RtaTeq (RV5) shuld be administered rally in a 3-dse schedule at the time f the DTP/penta1, DTP/penta2, and DTP/penta3 cntacts, with an interval f at least 4 weeks between dses. Because f the typical age distributin f RVGE, rtavirus vaccinatin f children >24 mnths f age is nt recmmended. Prematurely brn infants shuld fllw the vaccinatin schedules recmmended fr their chrnlgical age. Rtavirus vaccinatins can be administered simultaneusly with ther vaccines in the infant immunizatin schedule. Lifting f previus age restrictins: The vaccine manufacturers cnventinal age restrictins n the first and last dse f rtavirus vaccines may prevent vaccinatin f many vulnerable children in settings where the DTP dses are ften given late (i.e. after 15 weeks fr DTP/penta1; r after 32 weeks fr DTP/penta2 r DTP/penta3) 3. WHO s recmmendatin encurages early vaccinatin (first dse t be given at, r as sn as pssible after, 6 weeks f age) but allws infants t receive rtavirus vaccine tgether with DTP/penta regardless f the time f vaccinatin. This means children wh were previusly excluded frm the benefits f rtavirus vaccines are nw eligible t be vaccinated. Nevertheless, since rtavirus is a disease that affects yung infants, the intrductin f rtavirus vaccine shuld be accmpanied by measures t ensure high vaccinatin cverage and timely administratin f each dse in rder t maximize the benefit. Plans fr intrductin f rtavirus vaccines shuld cnsider the epidemilgy f the disease by age, the cverage and actual age at vaccinatin and an evaluatin f the estimated public health impact and ptential risks. In additin, cst-effectiveness assessment, issues f affrdability f the vaccine, financial and peratinal impact n the immunizatin delivery system, and careful examinatin f current immunizatin practices shuld be taken int accunt This crrespnds t the schedule used in the clinical trials fr licensure. 6 I ntrductin f Rtavirus vaccines

8 Need fr a cmprehensive apprach: The use f rtavirus vaccines shuld be part f a cmprehensive strategy t cntrl diarrheal diseases with the scaling up f bth preventin (prmtin f early and exclusive breastfeeding fr six mnths, vitamin A supplementatin, hand-washing, imprved water supply and sanitatin) and treatment services. WHO/UNICEF recmmend that all children receive slutins f lw-smlarity ORS t prevent and treat dehydratin due t diarrhea. Breast milk is als an excellent rehydratin fluid and shuld be given t children still breastfeeding, alng with ORS. In additin t fluid replacement, children with diarrhea shuld cntinue t be fed during the episde. Fd intake supprts fluid absrptin frm the gut int the bldstream t prevent dehydratin and helps maintain nutritinal status and the ability t fight infectin. Children shuld als simultaneusly receive zinc treatment which reduces the duratin and severity f diarrhea episdes, stl vlume and the need fr advanced medical care. Vaccine safety: Apart frm a lw risk f intussusceptin (abut 1 2 per infants vaccinated), the current rtavirus vaccines are cnsidered safe and well tlerated. Cuntries shuld develp a strategy t infrm relevant health staff that althugh the benefits utweigh the risks, a small ptential risk f intussusceptin after rtavirus vaccinatin remains. Cuntries shuld als ensure that caregivers are adequately cunseled t recgnize danger signs f dehydratin r intussusceptin that require immediate medical attentin. Prper planning and training f staff t cnduct pharmacvigilance shuld take place befre the vaccine is intrduced. Given the backgrund rate f natural intussusceptin and the large number f children included in natinal immunizatin prgrammes, intussusceptin cases are expected t ccur by chance alne fllwing rtavirus vaccinatin. It is imprtant t establish the baseline incidence f intussusceptin at sentinel sites and t use epidemilgical studies, such as the self-cntrlled case series methd 4, t assess the safety f rtavirus vaccines.* Cntraindicatins: Severe allergic reactin (e.g. anaphylaxis) after a previus dse, and severe immundeficiency including severe cmbined immundeficiency (SCID), are cntraindicatins fr rtavirus vaccinatin. Precautins are necessary if there is a histry f intussusceptin r intestinal malfrmatins, chrnic gastrintestinal disease, and severe acute illness. Vaccinatin shuld be pstpned in case f nging acute gastrenteritis r fever with mderate t severe illness. Surveillance: The epidemilgical impact f rtavirus vaccinatin shuld be mnitred. High-quality surveillance shuld be cnducted in selected cuntries and defined ppulatins, including high child mrtality settings. Hwever, lack f surveillance shuld nt be an impediment t the intrductin f rtavirus vaccine. * See WER, N. 8, 2011 pp Andrews, N. Epidemilgical designs fr vaccine safety assessment: methds & pitfalls. Bilgicals Sep;40(5):389-92; and Glbal Advisry Cmmittee n Vaccine Safety (GACVS). Glbal Safety f Vaccines: Strengthening systems fr mnitring, management and rle f GACVS. Expert Rev.Vaccines (6), I ntrductin f Rtavirus vaccines

9 Overview f the planning prcess TEN KEY ELEMENTS OF A SUCCESSFULL NATIONAL PLAN FOR THE INTRODUCTION AND IMPACT EVALUATION OF ROTAVIRUS VACCINES Element f the planning prcess Why? What is knwn? Further reading Planning element 1 Analyze the epidemilgy f rtavirus disease in yur cuntry (e.g. age distributin f rtavirus gastrenteritis) Need t knw the age distributin f RVGE in yur cuntry (r in similar r neighburing cuntries) t ensure that the infants are prtected befre they are infected with rtavirus. Rtaviruses (RVs) are glbally the leading cause f severe, dehydrating diarrhea in yung children. Mst children are infected by the age f 3-5 years regardless f the place where they are brn. Severe rtavirus gastrenteritis (RVGE) episdes and deaths ccur mre frequently in lw-incme cuntries and mainly affect infants under ne year f age. Children in lw-incme cuntries acquire their first infectin early during the first year f life and the mean age at infectin is arund 26 weeks f age. Page 10 Planning element 2 Review the age at which children are receiving each dse f DTP /pentavalent vaccine (timeliness) and, the cverage achieved Rtavirus vaccine dses need t be administered in a timely manner and, it is imprtant t achieve high cverage with each dse f vaccine. Vaccinatin shuld be initiated as early as pssible (i.e. at 6 weeks f age r sn thereafter). This is especially imprtant fr rtavirus vaccine as many children will be expsed t rtavirus during the first mnths f life. Therefre, the intrductin f rtavirus vaccine shuld be accmpanied by measures t ensure high vaccinatin cverage and timely administratin f each dse by the recmmended age. Page 12 Planning element 3 Review cverage at subnatinal level and, identify areas where cverage is lwer than natinal targets Rtavirus vaccine cverage needs t be high amng children at greatest risk f dying frm RVGE. These children ften live in areas with pr access t health services. Activities arund rtavirus vaccine intrductin ffer an pprtunity t: identify lw perfrming areas; ascertain reasns why children remain unvaccinated and; implement as part f the rtavirus vaccine intrductin plan, specific actins t remediate any gaps in rutine immunizatin; supprt an integrated apprach t the preventin f diarrhea (and pneumnia) Page 14 8 I ntrductin f Rtavirus vaccines

10 Planning element 4 Select the vaccine and vaccinatin schedule that is mst suitable fr yur cuntry Vaccinatin shuld be scheduled as early as pssible; and this is especially imprtant fr rtavirus vaccine as many children will be expsed t rtavirus during the first mnths f life. Tw safe and effective ral rtavirus vaccines, Rtarix (RV1) and RtaTeq (RV5), are prequalified by WHO. The currently available efficacy and safety data supprt selectin f either f these tw vaccines fr natinal use. A large number f randmized, cntrlled trials have shwn that bth have 80%-90% efficacy against severe RVGE in cuntries with very lw r lw child and adult mrtality, and have 40% - 60% efficacy in cuntries with high child mrtality and high r very high adult mrtality. 5 Administering rtavirus vaccine at the same cntacts as DTP/penta can help maintain high cverage and ensure that mre children benefit frm rtavirus vaccine. Page 16 Planning element 5 Assess the lgistic implicatins f yur vaccine and schedule selectin T successfully integrate rtavirus vaccine int the natinal vaccinatin schedule, existing cld chain and lgistic systems will likely need t be adjusted. Lgistics systems shuld be adjusted t include prper sessin planning, vaccine frecasting, strage and wastage mnitring f this additinal new vaccine. Expanding needs fr cld chain and transprt capacity at all levels f the supply chain shuld be anticipated and addressed. Page 19 Planning element 6 Review and discuss ther peratinal factrs that are relevant in yur cuntry T determine ther equally imprtant peratinal cnsideratins that shuld be well-thughtut during planning fr a successful implementatin. Additinal issues shuld be taken int accunt including: ther key activities planned during the year, ptential peratinal impact f the rtavirus vaccine intrductin n the immunizatin delivery system, and careful examinatin f current immunizatin practices. Prir t the intrductin f any new vaccine it is imprtant t identify the training needs at all levels, ensure that the data recrding instruments have been updated t include recrding f rtavirus vaccine dses, and strengthen supervisry skills s that adequate supprt is given t staff during the intrductin perid and thereafter. Page 20 Planning element 7 Rtavirus vaccine prtects against ne cause f diarrhea, but nt all causes. Diarrhea and pneumnia remain the majr killers f yung children. Tgether, these diseases accunt fr 29% f all deaths f children less than 5 years f age and the lss f an estimated 2 millin lives each year. Page 22 Plan integrated actins fr the preventin and cntrl f diarrhea (and pneumnia) Preventin f childhd diarrheal disease als needs imprved cverage f exclusive 6 mnths breastfeeding; vitamin A supplementatin; safe water, hand washing with sap and sanitatin; and use f ORS and zinc treatment. Better crdinatin and integratin between prgrammes that deliver the different interventins t prevent, prtect and treat are fundamental t tackling pneumnia and diarrhea. The determinants that underlie these tw diseases are ften the same. The children at risk f diarrhea are the same nes at risk f pneumnia. If planned prperly, the intrductin f rtavirus vaccine can help strengthen systems fr the delivery f the ther diarrhea (and pneumnia) interventins (integrated lgistics, training, etc.). 5 See Table 1 f the Dec 2009 psitin paper 9 I ntrductin f Rtavirus vaccines

11 Planning element 8 Identify activities t establish/ enhance rtavirus disease surveillance system and t mnitr and evaluate prgress with implementatin f rtavirus vaccine The epidemilgical impact f rtavirus vaccinatin shuld be mnitred ver time, t dcument the prgress made and infrm adjustments in plicy as apprpriate. Mnitring and evaluatin are essential t assess hw well a public health prgramme is functining and what impact it is achieving. High-quality surveillance shuld be cnducted in selected cuntries and defined ppulatins, including high child mrtality settings. Hwever lack f surveillance shuld nt be an impediment t rtavirus vaccine intrductin. Bth mnitring and evaluatin generate data that can be used t imprve prgramme planning and management. Page 24 Planning element 9 Prepare a plan t mnitr and investigate any adverse events fllwing immunizatin (AEFI) A plan fr mnitring f AEFIs and training f staff that will be respnsible fr AEFI mnitring shuld be in place befre the vaccine is intrduced. In large cntrlled trials, n differences were bserved between the vaccine grups and the placeb grups in terms f serius adverse events. Hwever, in sme, but nt all settings, pst-marketing surveillance has detected a small increased risk f intussusceptin (abut 1 2 cases/ infants vaccinated) shrtly after the first dse. Still, the benefits that rtavirus vaccinatin prvides, thrugh preventin f severe diarrhea and death frm rtavirus infectin, far exceed the risk f intussusceptin. Cuntries shuld develp a strategy t infrm relevant health staff that althugh the benefits utweigh the risks, a small ptential risk f intussusceptin after rtavirus vaccinatin remains. Page 26 Health staff must be encuraged t strengthen the detectin, reprting and investigatin f intussusceptin cases and RVGE cases t further assess risks and benefits f this vaccine 6. Planning element 10 Prepare an intrductin plan at natinal level and facilitate the develpment f district and lcal level micr-plans fr rtavirus vaccine intrductin When intrducing a new vaccine int rutine childhd immunizatin schedules, prper planning t accmmdate the varius aspects f a new vaccine is crucial fr successful intrductin. A detailed intrductin plan including all required activities and adjustments t the immunizatin prgramme is required fr an rderly and successful intrductin f rtavirus vaccine. The intrductin plan shuld be accmpanied by specific micr-plans at sub- natinal level that describe the activities, timelines and staff respnsibilities at different levels in detail. The rtavirus intrductin plan shuld be integrated int the natinal cmprehensive multi-year plan fr immunizatin (cmyp) and benefit frm the technical inputs f the Natinal Immunizatin Technical Advisry Grup (NITAG) and supprt frm the Inter-Agency Crdinating Cmmittee (ICC) and ther relevant stakehlders. Page 28 6 Bines, J.E., et al, Validatin f clinical case definitin f acute intussusceptin in infants in Viet Nam and Australia. Bulletin f the Wrld Health Organizatin 2006;84: I ntrductin f Rtavirus vaccines

12 Planning element rtavirus 1 disease Analyze the epidemilgy f in yur cuntry r in similar settings It is estimated that nearly all children will be expsed t rtavirus befre 3-5 years f age, regardless f where they are brn. Rtaviruses are the leading cause f severe, dehydrating diarrhea in children aged <5 years glbally. Children in lwincme cuntries acquire the infectin early during the first year f life and the median age at the primary rtavirus infectin ranges frm 6 t 9 mnths (80% ccur amng infants <1 year ld). In high incme cuntries, the first episde may be delayed until the age f 2 5 years, thugh the majrity still ccur in infancy (65% ccur amng infants <1 year ld) 7. The percentages f all rtavirus gastrenteritis (RVGE) cases in children 3 years ld which are estimated t ccur by a given age are: Age in weeks % f RVGE cases in children 36 mnths f age by 6 weeks 1% by 9 weeks 3% by 13 weeks 6% by 15 weeks 8% by 17 weeks 10% by 26 weeks 22% by 32 weeks 32% Hwever, there are substantial differences amng cuntries. In additin, data suggest that children in the prest, typically rural, husehlds with the highest risk f mrtality may have the earliest expsure t rtavirus. KEY TASKS Knw the age distributin f the RVGE in yur cuntry (r in similar r neighburing cuntries) t ensure that the infants are prtected befre they are infected with rtavirus. 1. If available, assemble existing natinal data n the age distributin f RVGE cases and deaths: Use available data frm natinal surveillance netwrk r sentinel sites; Identify lcal researchers wrking in-cuntry thrugh literature review and infrmal methds and cntact them t btain additinal data. 2. Analyze the data using narrw agegrups, particularly fr infants (e.g. < 1 mnth, 1-5 mnths, 6-11 mnths, mnths, mnths, > 24 mnths f age). 3. If available, cmpare age distributins fr RVGE admissins with thse fr RVGE deaths, RVGE cases in the cmmunity, and any diarrhea. 4. Cmpare the age distributins using different ptential mdifiers (e.g. gegraphic area, urban and rural settings etc.). 5. If yu cannt identify lcal data, use reginal r glbal reviews r rtavirus epidemilgy. The fllwing website can prvide yu with access t such data ( 7 Sandersn C et al (2011). Glbal review f rtavirus mrbidity and mrtality data by age and WHO regin. Reprt t WHO/IVB I ntrductin f Rtavirus vaccines

13 Belw is the age distributin f rtavirus gastrenteritis deaths by WHO Mrtality Stratum 8. In Stratum D (high child and high adult mrtality) the peak f the estimated deaths is apprximately 26 weeks f age. Examples f age distributin f rtavirus gastrenteritis cases in sme cuntries are presented 6. African Regin (AFR) Regin f the Americas (AMR) 8 WHO subregins are stratified (A thrugh E) based n levels f child and adult mrtality: Stratum A, very lw child and very lw adult mrtality; Stratum B, lw child and lw adult mrtality; Stratum C, lw child and high adult mrtality; Stratum D, high child and high adult mrtality; Stratum E, high child and very high adult mrtality. Please cnsult the List f Member States by WHO regin and mrtality stratum available at accessed January I ntrductin f Rtavirus vaccines

14 Eastern Mediterranean Regin (EMR) Eurpean Regin (EUR) 13 I ntrductin f Rtavirus vaccines

15 Suth East Asian Regin (SEAR) Western Pacific Regin (WPR) 14 I ntrductin f Rtavirus vaccines

16 If analysis shws that in yur cuntry rtavirus cases ccur mstly in yung infants yu shuld include actins in yur plan t ensure that all dses are given n time in rder t have the maximum prtective impact f vaccinatin. This may invlve planning training fr health wrkers n the need t vaccinate n time and the use f active defaulter tracking, as well as strng interpersnal skills t explain t caregivers the imprtance f returning n time fr ther dses. Effective cmmunicatin and scial mbilizatin effrts will be very imprtant. Gd supervisin and n-ging mnitring f data will als be necessary. 15 I ntrductin f Rtavirus vaccines

17 Planning element 2 Review the age at which children are receiving each dse f DTP/pentavalent vaccine (timeliness) and the cverage achieved The immunizatin schedule defines the minimum age fr receipt f vaccines. It is imprtant t take effective steps t ensure all vaccinatins are given at the recmmended age and nt delayed. Althugh the cverage achieved with each dse f DTP/penta by 12 mnths f age in a cuntry may be > 80%, it is imprtant t establish what prprtin f thse children did nt receive their dses f DTP/penta vaccines at the recmmended ages (i.e. n time ). Rtavirus vaccine can be given t infants at any age, alng with the DTP/penta vaccine dses. The first dse shuld be administered at 6 weeks f age r sn thereafter. Frequently a significant prprtin f children d nt receive their dses n time r early enugh, thus leaving them unprtected r inadequately prtected during the time perid where the risk f rtavirus infectin and disease is greatest. Mrever, DTP/pentavalent cverage amng infants at the highest risk f death (e.g. lwest sci-ecnmic level) is ften lwer than the natinal average. Implementing strategies t reduce the number f unvaccinated children and/r children vaccinated late is imprtant fr rtavirus vaccine and als fr strengthening the verall perfrmance f the prgramme. KEY TASKS Rtavirus vaccine dses need t be administered in a timely manner and it is imprtant t achieve high cverage with each dse f vaccine. 1. Gather existing natinal data n actual age f DTP/penta vaccinatin, timeliness and cverage fr each dse f DTP/penta vaccine: Use available data frm natinal cverage reprts r frm cverage surveys; Identify lcal cverage surveys thrugh literature review and infrmal methds; Analyze the timeliness and cverage data using narrw age-grups, particularly fr infants (e.g. < 2 mnth, 2-5 mnths, 6-11 mnths, mnths, mnths f age). 2. Cmpare cverage and timeliness f each dse by gegraphic area, urban and rural settings, sciecnmic status etc. 3. If yu cannt identify lcal data frm surveys, use reginal r glbal reviews f DTP/penta cverage r review the data included in this website ( 16 I ntrductin f Rtavirus vaccines

18 Health educatin and mass mbilizatin f the cmmunity are essential nt nly t increase the cverage but als fr the timely receipt f vaccines. Timely cmmencement f immunizatin and cmpletin f the schedule shuld be emphasized. Health wrkers need t be trained t nt miss any pprtunity t vaccinate children cming t health facilities fr any reasn and, t implement strategies t reach infants wh d nt have regular access t immunizatin services (e.g. utreach, peridic intensificatin f rutine immunizatin (PIRI), etc). Strategies t imprve the timeliness f vaccinatin: 1. Messages t mthers/caregivers: At time f vaccinatin, ensure that health wrkers give clear infrmatin t mthers/caregivers abut when the child must return fr their next scheduled dse. 2. Health Facility Immunizatin Reminder Bx: Health wrkers can keep track f infants due fr vaccinatin by filing a cpy f the immunizatin card in a bx with dividers fr each mnth. If an infant received Rta1 in January, then a cpy f the card is placed in the February sectin. Every mnth, the health wrker can review the reminder cards and fllw up with thse wh did nt attend when due (e.g. active fllw-up f defaulters). 3. Regular Outreach Planning: Ensure that utreach sessins are carefully planned and implemented t enable children in these areas t get their vaccines n time. 17 I ntrductin f Rtavirus vaccines

19 Belw are sme examples f analysis f age at vaccinatin with each dse f DTP using data frm cverage surveys. 18 I ntrductin f Rtavirus vaccines

20 Planning element 3 Review immunizatin cverage at sub-natinal level and identify areas where cverage is lwer than natinal targets While childhd immunizatin cverage levels have increased since the 1980s, inequities in cverage within cuntries are cmmn. The intrductin f a new vaccine prvides the pprtunity t strengthen the verall immunizatin prgramme and, t increase cverage in lw perfrming areas. Natinal immunizatin prgrammes shuld estimate and mnitr the prprtin f unvaccinated children (i.e. thse wh have received n vaccines at all r with incmplete vaccinatin). Factrs that have been identified as strngly assciated with being unvaccinated include: educatin f the caregiver, educatin f caregiver's partner, caregiver's tetanus txid (TT) status, wealth index and type f family member participatin in decisin-making when the child is ill. An analysis f immunizatin cverage shuld be perfrmed as part f the rtavirus intrductin plan. It shuld fcus n subnatinal levels r areas where pr perfrmance is suspected. Natinal/subnatinal representative husehld surveys can prvide evidence n the specific factrs that influence access t immunizatin services. KEY TASKS Rtavirus vaccine cverage needs t be high amng children wh are at greatest risk f dying frm RVGE. 1. Analyze immunizatin cverage by sub-natinal levels fr the last 3 years. 2. Identify sub-natinal levels r areas where mst unvaccinated r partially unvaccinated children live. Fr example, using ppulatin and cverage data estimate the number f unvaccinated infants and srt the areas, listing first thse with greatest number f unvaccinated r partially unvaccinated children. 3. Discuss with relevant immunizatin staff in thse areas, and identify using a similar apprach, the areas within the sub-natinal level where the greatest number f unvaccinated r partially unvaccinated children live. 4. Use available infrmatin (r investigate) t identify the factrs that may be assciated with being unvaccinated in thse areas. 5. Identify activities that can address thse factrs and effectively reduce the number f unvaccinated children. 6. Ensure that the identified activities are reflected in the natinal plan fr intrductin and in the sub-natinal levels micr-plans. Natinal immunizatin prgrammes shuld develp specific plans t 19 I ntrductin f Rtavirus vaccines

21 address the determinants f nn-vaccinatin at natinal and sub-natinal levels. 20 I ntrductin f Rtavirus vaccines

22 T supprt cuntry level effrts t imprve immunizatin cverage, the "Reaching Every District" (RED) strategy was develped 9. RED is a strategy t achieve the gal f 80% immunizatin cverage in all districts and 90% natinally. RED aims t fully immunize every infant with all vaccines included in the natinal immunizatin schedule f cuntries. In rder t achieve this gal, the strategy fcuses n building natinal capacity frm district level upward t maximize access t all vaccines, ld and new. RED addresses cmmn bstacles t increasing immunizatin cverage such as pr quality district planning, lw quality and unreliable service, inadequate mnitring and supervisin f health wrkers. Descriptin f the five RED peratinal cmpnents 1. Re-establishing utreach services In many cuntries a large prprtin f the ppulatin can nly be reached regularly thugh utreach sessins. Outreach is any delivery strategy that requires health facility staff t leave their facility t deliver immunizatin. Ideally a minimum f fur cntacts per year are required t fully immunize an infant. Fr sme cmmunities, access can nly be prvided irregularly, and may require mbile teams t prvide utreach, which will invlve resurces beynd the health facility and district level. Outreach sessins, especially mbile teams present pprtunities t prvide ther interventins with immunizatin. 2. Supprtive supervisin Supprtive supervisin implies prviding n-site training t health wrkers at the time f a supervisry visit, r at regular district meetings. T be supprtive, supervisrs shuld make regular schedules fr visits, help t slve prblems lcally and fllw up regularly with supply and resurce issues. Supervisrs will themselves need training t adapt their wn appraches t supervisin. 3. Linking services with cmmunities Invlving the cmmunity with the planning and delivery f the service will encurage cmmunity wnership and imprve attendance. Identifying cmmunity vlunteers prviding them with a rle, such as fllw up f defaulters, and hlding regular meetings is an imprtant step twards building a link with the cmmunity. 4. Mnitring and use f data fr actin Mnitring and use f data fr actin implies nt nly the timely cllectin f data at district level, but the use f the data t slve prblems. Sme simple tls, including wall charts that display access and utilizatin, need little training, but are very useful t take actin accrding t mnthly prgress. Nt nly d districts cllect cverage data, but als a large amunt f ther infrmatin, including lgistics, supply, surveillance, all f which shuld be used t imprve the immunizatin system. Sme qualitative data may nt be available in regular reprts and may need t cllected thugh supervisry visits. 5. Planning and management f resurces The district micr plan is the key t the RED strategy. The micr plan shuld be based upn a lcal situatin analysis which invlves every health facility and thrugh them the cmmunity that they serve. At the natinal level, there is a respnsibility t ensure the needed financial and human resurces are available t the district, while the district must ensure the resurces are efficiently used, thrugh regular mnitring and adjusting the micr plan. Cntinuing t fund the RED strategy fr mre than the first year f implementatin is vital fr sustainability f cverage increase I ntrductin f Rtavirus vaccines

23 Planning element 4 Select the vaccine and vaccinatin schedule that is mst suitable fr yur cuntry Tw WHO prequalified ral rtavirus vaccines are marketed internatinally 10 : the mnvalent (RV1) Rtarix (GlaxSmithKline Bilgicals, Rixensart, Belgium) and the pentavalent (RV5) RtaTeq (Merck & C. Inc., West Pint, PA, USA). Currently available efficacy and safety data supprt selectin f either f the tw vaccines fr natinal use. Althugh bth rtavirus vaccines are efficacius, data shw that their efficacy is higher in settings with lw mrtality in children under five years f age (vaccine efficacy ~ 90%) than, in settings with high mrtality in children under five years f age (vaccine efficacy~ 60%). Because the incidence f rtavirus disease is significantly higher in high child mrtality settings, the number f severe disease and deaths averted by rtavirus vaccines in these settings is likely t be greater than in lw mrtality settings, despite the lwer vaccine efficacy. KEY TASKS Vaccinatin shuld be scheduled as early as pssible; and this is especially imprtant fr rtavirus vaccine as many children will be expsed t rtavirus during the first mnths f life. 1. Review the peratinal characteristics f the tw cmmercially available rtavirus vaccines. 2. Cnsider given the current natinal immunizatin schedule which vaccine culd be mre suitable fr yur cuntry (e.g. pprtunities t deliver during already established immunizatin cntacts, cld chain capacity, etc.). 3. Seek inputs frm the cuntry Natinal technical Advisry Grup (NITAG) n yur prpsed vaccine and schedule chices. Observatinal studies in cuntries that have already intrduced rtavirus vaccine have reprted a substantial reductin in disease burden within a few years after intrductin and als sme evidence f herd prtectin expressed as disease reductin in unvaccinated lder children and adults. Data als suggest that rtavirus vaccinatin has delayed the nset and decreased the size f the annual seasnal peaks f rtavirus disease. 10 Lanzhu lamb rtavirus vaccine, manufactured by the Lanzhu Institute f Bimedical Prducts in China, and Rtavin-M1, manufactured by Plyvac in Viet Nam, are nt available internatinally and therefre will nt be discussed here. 22 I ntrductin f Rtavirus vaccines

24 Table 1. WHO Recmmended Vaccinatin Schedules fr Rtarix and RtaTeq 11 Rtavirus Antigen Age f 1 st dse Dses in primary series Rtarix (RV1) Rtateq (RV5) 6 weeks (min) given with DTP1/penta1 6 weeks (min) given with DTP1/penta1 Interval between dses 1 st t 2nd 2 nd t 3rd 2 4 weeks (min) given with DTP2/penta2 3 4 weeks (min) given with DTP2/penta2 4 weeks (min) given with DTP3/penta3 Bster dse nne nne Rtavirus vaccinatins can be administered simultaneusly with ther vaccines in the infant immunizatin prgramme. The interchangeability f Rtarix and RtaTeq has nt been studied. Severe allergic reactin (e.g. anaphylaxis) after a previus dse, and severe immundeficiency including severe cmbined immundeficiency (SCID), are cntraindicatins fr rtavirus vaccinatin. Precautins are necessary if there is a histry f intussusceptin r intestinal malfrmatins, chrnic gastrintestinal disease, and severe acute illness. Vaccinatin shuld be pstpned in case f n-ging acute gastrenteritis r fever with mderate t severe illness until the child recvers. The presence f minr infectins, hwever, is nt a cntraindicatin fr vaccinatin. Current rtavirus vaccines are generally well tlerated. They d nt appear t cause any serius adverse events. A small prprtin f infants receiving the vaccine may suffer shrt episdes f mild diarrhea, vmiting r fever in the week fllwing vaccinatin. Intussusceptin was fund t be a rare but significant side effect f the first generatin rtavirus vaccine (RtaShield ) that was available in the United States in but is n lnger available. The new vaccines Rtarix and RtaTeq were bth tested in large studies designed t exclude a risk f intussusceptin similar t RtaShield. In these studies n increased risk f intussusceptin was bserved. As even large pre-registratin safety studies cannt detect rare events, pst-marketing studies have been undertaken in a number f cuntries. Apart frm a lw risk f intussusceptin (abut 1 2 per infants vaccinated) the current rtavirus vaccines are cnsidered safe and well tlerated (fr mre infrmatin see Annex 4). 11 Fr mre infrmatin please refer t: I ntrductin f Rtavirus vaccines

25 Planning element 5 Assess the lgistic implicatins f yur vaccine and schedule selectin The natinal immunizatin manager shuld assess the available vaccine frmulatin ptins (lyphilized/liquid) and presentatin (type f prefilled ral applicatr/tube) with respect t immunizatin prgramme s requirements. Factrs that need t be cnsidered during the selectin include: number f ther vaccines administered per visit cld strage space available and additinal needs VVM n the label vaccine wastage (e.g. fr Rtateq which has n VVM) staff training and supervisin recrding and reprting mechanisms prgramme csts, nt just fr the price f the vaccine but fr the prgrammatic/peratinal csts f the different ptins and, the sustainability ver time. KEY TASKS T successfully integrate rtavirus vaccine int the natinal vaccinatin schedule, existing lgistic systems may need t be adjusted. 1. Review the peratinal characteristics f the cmmercially available prequalified rtavirus vaccines. 2. Evaluate any vaccine supply cnsideratins in the shrt and lng term. 3. Assess any budget implicatins f yur chice f vaccines (e.g. vaccine price, peratinal and lgistics csts assciated). 4. Seek inputs frm the cuntry Natinal technical Advisry Grup (NITAG) n yur prpsed adjustments t lgistics and ther key issues. The assessment shuld lead t a decisin n ne r mre preferred ptins. The results shuld include a summary f a ranking f ptins, criteria cnsidered during the selectin prcess, as well as planning f the steps t tackle any issues/cnstraints. The tw available rtavirus vaccines differ in peratinal characteristics which are summarized in Table 2 belw. These different vaccine characteristics shuld be carefully cnsidered within the cntext f the current natinal immunizatin prgramme, infant immunizatin schedule, infrastructure, and budget in rder t select the mst apprpriate vaccine fr the cuntry. All fur presentatins f rtavirus vaccine require additinal space fr transprt and strage in the cld chain (see Annex 2). 24 I ntrductin f Rtavirus vaccines

26 Table 2. Imprtant attributes f cmmercially available Rtavirus vaccines 12 GSK Rtarix - mnvalent, human strain, live, attenuated, ral rtavirus vaccine Vaccine type RV1 is a live vaccine Rute f administratin Immunizatin schedule Dse Shelf life Strage requirements Presentatin Vaccine picture Oral 2-dse schedule, given with first and secnd dses f DTP/penta. Each dse cntains a suspensin f at least the median cell culture infective dse (CCID50) -- f live, attenuated human G1P[8] rtavirus particles. The vaccine shelf-life is 36 mnths. Shuld be kept at 2 8 C, prtected frm light, and shuld nt be frzen. Liquid Rtarix in ral applicatr (single dse) Liquid Rtarix in squeezable plyethylene tube (single dse) Lyphilized Rtarix vaccine recnstituted with CaCO3 buffer (single dse) Administratin Administered rally using the applicatr. Administered rally using the applicatr. Recnstituted and administered rally using the applicatr. Vlume per dse Packaging 1.5 ml 1.5 ml 1 ml 1 and 10 single-dse ral applicatrs per pack. 1,10, r 50 single dse tubes per pack 1 and 10 single-dses per pack. The vaccine is packed tgether with diluent and shuld be stred as such. Significant cld chain vlume implicatins (156 cm3/dse) Strage vlume See Annex 3 See Annex 3 See Annex 3 Vaccine vial mnitr Surce It has a VVM 14 It has a VVM 14 It has a VVM 14 Surce: GSK Bilgicals 12 Further infrmatin may be fund n the fllwing website: 25 I ntrductin f Rtavirus vaccines

27 Merck RtaTeq - pentavalent, human-bvine reassrtant strain, live, attenuated, ral, rtavirus vaccine Vaccine type RV5 is a live vaccine Rute f Oral administratin Immunizatin 3-dse schedule, given with three dses f DTP/penta. schedule Dse Each dse (2 ml) f the vaccine cntains a minimum titre f apprximately x 10 6 infectius units per reassrtant, and nt greater than 116 x 10 6 infectius units per aggregate dse. Shelf life The vaccine shelf life is 24 mnths. Strage Shuld be stred at 2 8 C, prtected frm light and shuld nt be frzen. requirements Fllwing remval frm refrigeratin, the vaccine shuld be used as sn as pssible. Presentatin One presentatin: ral squeezable tube (single dse) Vaccine picture Administratin Vlume per dse Packaging Administered rally using the squeeze tube. 2 ml/dse Available in cartns f 1,10, 25 single-dse tubes per pack Significant cld chain vlume implicatins. Strage vlume See Annex 3 Vaccine vial The vaccine tubes d nt have VVMs. mnitr Surce Surce: Merck & C. 26 I ntrductin f Rtavirus vaccines

28 Planning element 6 Review and discuss ther peratinal factrs that are relevant in yur cuntry T successfully integrate rtavirus vaccine int the natinal vaccinatin schedule, existing systems may need t be mdified 13. It will be useful t cnsider the additinal pints belw when updating a cuntry multi-year plan (cmyp) t include rtavirus vaccine intrductin: supply needs cld-chain readiness vaccine wastage (e.g. fr Rtateq which des nt have a VVM) revisin f recrds and reprting tls staff training and supervisin infrmatin, educatin and cmmunicatin Supply needs Estimate the number f dses f rtavirus vaccine needed per year. The prcess fr estimating the number f vaccine dses needed is similar t ther vaccines. In the frecasting f vaccine needs, safety stck (als referred t as buffer stck) shuld be adequate t cver unexpected delays in shipments and fluctuatins in demand. Since rtavirus vaccines are rally administered, syringes and equipment fr safe needle dispsal are nt required and therefre d nt need t be calculated. KEY TASKS Determine ther equally imprtant peratinal cnsideratins that shuld be well-thught-ut during planning fr a successful implementatin. 1. Organize a sessin with key staff at natinal level (and representatives frm the subnatinal levels if feasible) t identify key peratinal issues related t the intrductin f rtavirus vaccines. 2. Review current practices t mnitr vaccine wastage and waste dispsal and plan activities t ensure rtavirus vaccine wastage is mnitred at all levels. 3. Organize/prmte refresher training fr staff at all levels n special aspects f rtavirus vaccine and use the pprtunity t reinfrce knwledge f ther key immunizatin practices. 4. Prepare a cmmunicatin plan including activities t increase demand generatin and cmmunity messaging f benefits and ptential risks. 5. Prmte/ supprt the develpment f micr-plans in all sub-natinal levels. Cld strage and transprt readiness 13 Vaccine Intrductin Guidelines. Adding a vaccine t a natinal prgramme: decisin and implementatin I ntrductin f Rtavirus vaccines

29 Review current strage and transprt capacity in the cld chain and assess if additinal capacity is required and at which level. As mentined abve, as with any new vaccine intrductin, the intrductin f rtavirus vaccine requires additinal cld chain and transprt capacity (see Annex 1 and 2 fr a detailed summary f vlume per dse fr all available prducts). It is imprtant that a cmprehensive assessment and gap analysis f the strage space at all levels is carried ut nce the decisin has been made t intrduce rtavirus vaccine. Such an analysis shuld be dne as early as pssible in rder t have sufficient time t fund, prcure, receive and install new equipment befre vaccine intrductin. The use f digital temperature mnitring devices, such as fridge tags and lg tags, is strngly recmmended at natinal and sub-natinal levels t accurately recrd any excursins utside the recmmended temperature range f 2 t 8 C and develp and implement measures t prevent their recurrence. Mnitring f the cld chain Rtavirus vaccine shuld be stred and transprted at 2 t 8 C frm receipt at natinal level t its final pint f administratin t infants. Maintaining temperatures within this range is critical t prtect the ptency f the vaccine. These vaccines shuld nt be expsed t sub-zer temperatures, and all frzen water packs shuld be prperly cnditined prir t packing in cld bxes r vaccine carriers. If the vaccines are stred at WHO recmmended temperatures, the vaccines have a shelf-life f tw r three years (depending n the prduct) frm the pint f manufacture. At strage pints, temperatures shuld be recrded twice daily n a mnitring chart and crrective actin taken immediately if there is a cld chain failure. Establishing an effective temperature mnitring and recrding system f cld chain perfrmance is particularly critical in cases where the chsen vaccine des nt have a VVM. Expsure t high temperatures des nt result in any visual difference t the prduct. In the absence f a VVM, there is n means t determine the extent f heat damage which can ccur at multiple pints in the distributin chain. It is, therefre, extremely imprtant that cld chain cnditins are rigrusly maintained and clsely mnitred bth during strage and transprt frm vaccine receipt t vaccine administratin. Fr rtavirus vaccine furnished withut VVMs (Rtateq ), it is highly recmmended t use cntinuus temperature mnitring devices t stre and transprt vaccines under cld chain cnditins as specified by the manufacturer. Any break in the cld chain shuld be recrded and immediately reprted thrugh the supervisry channels. VVMs attached t ther vaccines cannt be used as a prxy t determine the cumulative level f heat expsure experienced by RtaTeq. In situatins where cntinuus temperature mnitring devices are nt available, the fllwing is recmmended: Discard unpened tubes immediately if there is a cmplete and sustained rupture in the cld chain and the ambient temperature exceeds 25 C; Discard unpened tubes if there is a temprary rupture in the cld chain and the vaccine is expsed t temperatures between 9 t 25 C fr mre than 36 cnsecutive hurs; 28 I ntrductin f Rtavirus vaccines

30 Discard unpened vaccine tubes at the end f utreach r mbile sessins if there is n assurance that the cld chain was maintained. Vaccine wastage Wastage rates shuld be rutinely mnitred fr all vaccines. It is imprtant t minimize wastage. In additin t saving funds, mnitring and preventing wastage can be an indicatr f gd prgramme management, especially relevant it the vaccine being used des nt have a VVM. In cuntries with a dispersed ppulatin and extensive utreach, a higher wastage rate may be acceptable in rder t achieve and maintain high cverage levels. Therefre, the apprpriate gal is wastage ptimizatin, which means t minimize preventable wastage withut cmprmising cverage r safety. The tw currently available rtavirus vaccines are packaged as single-dse presentatins fr ral administratin. Fr single-dse presentatins, the wastage rate when administering the vaccine is negligible. Hwever, fr planning purpses a wastage rate f up t a maximum f 1% 14 per strage pint can be used fr the estimatin f needs. This 1% wastage rate is set by EVM 15 t accunt fr unexpected unpened wastage during handling peratins in the supply chain. Fr any part f the supply chain, the anticipated wastage rate fr planning purpses shuld nt exceed the number strage levels times(x) 1%. In mst cuntries, fr the natinal level the wastage rate will nt exceed 5%. If the wastage rate fr rtavirus vaccine begins t increase natinally r in specific subnatinal lcatins, an investigatin shuld be undertaken t ascertain the reasn fr the increase. Waste Dispsal Used rtavirus vaccine ral applicatrs r squeeze tubes shuld be dispsed f in the same manner as ther vaccine vials are discarded and in accrdance with natinal waste management guidelines. Revisin f recrds and reprting tls 16 The main recrding tls that are used fr immunizatin-related activities shuld be adapted/revised t include rtavirus vaccine. At the service delivery level these include: Immunizatin r child health card Tally sheet Register Defaulter tracking system Stck recrd Integrated mnthly reprt. Immunizatin r child health card The card may be the nly recrd f immunizatin histry and status available fr health wrkers if the facility registers d nt exist r if clients mve frm ne health facility t anther. Each child shuld have a card with the rtavirus vaccine dses marked clearly with dates f administratin (nt tick marks). Tally Sheet 14 Wastage culd be higher if vaccine des nt have a VVM. 15 Effective Vaccine Management (EVM) Initiative Fr further infrmatin n immunizatin mnitring see Training fr Mid-Level Managers (MLM). Mdule 5: Mnitring the immunizatin system. WHO.2008 and Immunizatin in Practice: A Practical Guide fr Health Staff (2004 Update). WHO I ntrductin f Rtavirus vaccines

31 Tally sheets are the frms that health wrkers use t dcument an immunizatin sessin, by making a recrd fr every dse f vaccine given. Tally sheets shuld be used fr all sessins whether fixed, utreach r cnducted by mbile teams. It is always wrthwhile fr a supervisr t spend time reviewing tally sheets with staff t imprve the quality f reprting. Tally sheets need t be adapted t include rtavirus vaccines. Immunizatin Register While tally sheets recrd the dses given fr each sessin, the immunizatin register recrds dses given t each individual and helps health wrkers keep track f the immunizatin services that they have given each child (and pregnant wman). The register shuld be adapted s that the same can be dne fr each dse f rtavirus vaccines. Each dse f rtavirus vaccine given t every child in the catchment area shuld be recrded against their names in the register. In this way, the immunizatin register is the basis fr tracking individual immunizatin status (if, fr example, the child health r vaccinatin card is lst), and fr tracking defaulters. Staff training and supervisin The intrductin f a new vaccine prvides an pprtunity fr training health care wrkers n administering the new vaccine, while als prviding the pprtunity fr refresher training n ther vaccine-related issues, such as the cld chain, waste management, cmmunicatin with the ppulatin, etc. Apprpriate training and temperature mnitring practices shuld be enfrced t prmte prper vaccine handling at all stages f the cld chain. As with any new vaccine intrductin plan, fr the intrductin f rtavirus vaccine, immunizatin prgramme managers at natinal and sub-natinal levels must determine whse wrk will be affected and hw. Training f health wrkers The fllwing key issues shuld als be cnsidered in preparing fr health-wrker training: It is imprtant t familiarize health wrkers with relevant issues cncerning rtavirus infectin and the new vaccine since they will need t cmmunicate effectively with cmmunity leaders, parents and ther members f the public cncerning these tpics. Frequently Asked Questins are prvided in Annex 7. Health wrkers shuld be trained n the crrect way t stre the vaccine, which is sensitive t freezing. They shuld als be trained n hw t prperly administer the full vlume f the vaccine thrugh the ral rute, taking time t assist the infant t swallw. Package inserts frm each manufacturer cntain helpful details n administering the vaccines. Further infrmatin n vaccine administratin is shwn in Annex 8: Rtavirus Vaccines: A Pcket Guide fr Health Wrkers. In cuntries that intrduce mnvalent lyphilized rtavirus vaccine, it is imprtant t ensure that health wrkers receive clear instructins n the crrect practice fr recnstituting the lyphilized frmulatin, and/r administering rtavirus vaccine, and subsequent supervisin in the field, until they becme familiar with using the new vaccine. Health wrkers will need t make adjustments in rder t include rtavirus vaccinatins in rutine recrding and reprting practice. After training and nce the new vaccine has been intrduced, supervisrs shuld rutinely ensure that staff are fllwing the recmmended practices that they have been taught. If standards are nt met, supervisrs shuld address and help staff reslve any bstacles. 30 I ntrductin f Rtavirus vaccines

32 Advcacy, Cmmunicatin and Scial Mbilizatin In rder t assure gd uptake and acceptability, effective advcacy, cmmunicatin and scial mbilizatin activities need t be planned and implemented as part f rtavirus vaccine intrductin (Annex 6). It is best practice t develp an advcacy and cmmunicatins plan. The cmmunicatins plan and subsequent activities, materials, and messages will be mst effective if they are infrmed by a study f the public s knwledge, attitudes, beliefs and practices (KABP) abut rtavirus disease, rtavirus vaccine, and immunizatin in general. KABP studies can range frm a series f fcus grup discussins t mre invlved cmmunity and husehld surveys. They shuld target a range f different grups, including cmmunity and pinin leaders, teachers, health wrkers, and parents. The study can identify gaps in the public s knwledge and attitudes abut diarrhea, misperceptins and cncerns abut receiving rtavirus vaccine, and ther factrs that may affect the public s acceptance and thus uptake f the vaccine, such as the influence f anti-vaccinatin publicity. It is imprtant t develp materials tailred fr different target audiences and t use a range f different channels and media t deliver the messages. Obtaining the supprt frm and invlving respected plitical, religius and cmmunity leaders and a brad range f influential grups and members f sciety is vital t cmmunicate infrmatin t the cmmunity, t renew awareness f immunizatin, and t allay pssible safety cncerns abut rtavirus vaccine and t crrect misinfrmatin. Health wrkers are encuraged t build regular linkages with cmmunity leaders, lcal authrities and cmmunity mbilisers t raise awareness n the value f rtavirus vaccinatin and the imprtance f children receiving dses n time. The health wrker shuld advise cmmunity leaders f the time, date and lcatin f the next utreach/mbile visit, r the next scheduled immunizatin sessin at the fixed-site, and invite leaders t influence the attendance f families. Key messages fr health wrkers Many caretakers are familiar with the signs f diarrheal disease and will welcme the pprtunity t vaccinate their children t prevent ne f the imprtant causes f infant diarrhea and mrtality. Health wrkers shuld be equipped with apprpriate cmmunicatin tls t be able t explain key messages t the cmmunity. KEY MESSAGES FOR HEALTH WORKERS The infant must receive all dses f the vaccine t be fully prtected and he/she must cmplete the schedule as early as pssible (e.g. receive dses n time). Health wrkers shuld clearly cmmunicate the time, date and lcatin f the next utreach/mbile visit, r the next scheduled immunizatin sessin at the fixed-site, and encurage the caretakers' return. 31 I ntrductin f Rtavirus vaccines

33 The rtavirus vaccine prtects the infant against ne imprtant cause f diarrhea, but nt all causes. Therefre, a child vaccinated with Rtavirus vaccine may still get diarrhea frm ther agents. Preventin f childhd diarrheal diseases als requires imprvements in exclusive breastfeeding fr 6 mnths, vitamin A supplementatin, safe water, hygiene (such as handwashing with sap), and vitamin A supplementatin. If the infant suffers frm severe diarrhea, take him r her t the health center r cmmunity health wrker immediately t get treatment e.g. ral rehydratin slutin (ORS), zinc tablets, and cntinued feeding. Knw hw t recgnize the signs and symptms f intussusceptin in an infant (see Annex 5) and refer immediately t a health care facility fr treatment. 32 I ntrductin f Rtavirus vaccines

34 Planning element Plan integrated actins fr the preventin and cntrl diarrhea (and 7 pneumnia) KEY TASKS Rtavirus vaccine prtects against ne cause f diarrhea, but nt all causes. Therefre, the use f rtavirus vaccine needs t be part f a cmprehensive strategy t cntrl diarrheal diseases with the scaling up f bth preventin and treatment packages. The Integrated Glbal Actin Plan fr the Preventin and Cntrl f Pneumnia and Diarrhea (GAPPD) frm WHO and UNICEF (April 2013) 17 ges t the heart f this challenge: recgnizing that preventin and cntrl f pneumnia and diarrhea cannt be adequately dealt with separately but nly thrugh integrated prgrammes. WHO/UNICEF recmmend that all children receive slutins f lwsmlarity ral rehydratin slutin (ORS) t treat diarrhea. Breast milk is als an excellent rehydratin fluid and shuld be given t infants still breastfeeding, alng with ORS. In additin t fluid replacement, children with diarrhea shuld cntinue t be fed during the episde. Fd intake supprts fluid absrptin frm the gut int the bldstream t prevent dehydratin and helps maintain nutritinal status and ability t fight infectin. Children shuld als simultaneusly receive zinc treatment Identifying the children at greatest risk f dying frm diarrhea (and pneumnia), wh are the hardest t reach and the mst neglected, and targeting them with integrated appraches that are prven t wrk will clse the gap and end these entirely preventable deaths. 1. Cntact ther child health prgrammes/clleagues/partners engaged in the preventin and cntrl f diarrhea. 2. Review the status f implementatin and cverage f ther key interventins (e.g. exclusive breastfeeding fr 6 mnths, vitamin A supplementatin, safe water, hygiene (handwashing with sap) and sanitatin, ORS, zinc, and cntinued feeding fr treatment. 3. Jintly assess the bttlenecks and barriers t scaling up high cverage. 4. Use the pprtunity f rtavirus vaccine intrductin t crdinate and plan actins t imprve service delivery and demand fr all diarrhea (and pneumnia) interventins (e.g. supply chain, plicies, refresher training, materials, health educatin, etc). which reduces the duratin and severity f diarrhea episdes, stl vlume and the need fr advanced medical care. Therefre the rtavirus intrductin plan shuld include clear strategies and activities t facilitate the crdinatin f strategies at natinal level, the cnvergence f activities in the I ntrductin f Rtavirus vaccines

35 micr-plans at sub-natinal level, and the integratin f tasks at the service delivery level. 34 I ntrductin f Rtavirus vaccines

36 Planning element Identify activities t establish/enhance rtavirus disease surveillance and t mnitr and evaluate 8 the impact f rtavirus vaccine KEY TASKS Mnitring and evaluatin are essential t assess hw well a public health prgramme is functining and achieving its bjectives. Bth mnitring and evaluatin generate data that can be used t imprve prgramme planning and management. WHO recmmends that all cuntries that have intrduced rtavirus vaccine cnduct a pstintrductin evaluatin (PIE) six t 12 mnths fllwing intrductin. The purpse f the assessment is t evaluate the impact f intrductin n the cuntry s immunizatin prgramme and t rapidly identify prblems needing crrectin that are the result f the intrductin f rtavirus vaccine r that pre-existed it. The evaluatin can nt nly lead t imprvements in the implementatin f the new vaccine and verall immunizatin prgramme, but can als prvide valuable lessns fr future vaccine intrductins. WHO has prepared a user-friendly tl fr assessing new vaccine implementatin, which includes questinnaires and checklists that cuntries can adapt 18. The impact f rtavirus vaccinatin shuld be mnitred ver time, t dcument the prgress made and infrm adjustments in plicy as apprpriate. 1. Review prgress f yur intrductin plan with yur NITAG (6-12 mnths after vaccine intrductin) and assess whether r nt the plan is being implemented as prpsed. Cnduct a pstintrductin evaluatin (PIE) t: Identify areas f weak perfrmance r specific areas where further input may be needed and take actin t address them. Cllect infrmatin demnstrating success that can be used in future advcacy effrts that will supprt the lngterm sustainability f the prgramme. Identify the majr bttlenecks fr successful implementatin and prpse slutins as apprpriate. 2. Select a surveillance strategy and identify activities t establish/ strengthen rtavirus surveillance. 3. Incrprate int the vaccinepreventable diseases surveillance system the necessary activities t set in place surveillance f rtavirus disease. 4. Cntinue t review prgress regularly (e.g. each year). 18 The generic prtcl can be fund at: 35 I ntrductin f Rtavirus vaccines

37 Epidemilgical surveillance data are imprtant t guide decisins arund vaccine intrductin and use. Hwever, if cuntries have nt yet established rtavirus surveillance, this shuld nt be an impediment t the intrductin f rtavirus vaccine. Objectives f the surveillance system f diarrhea caused by rtavirus The main bjectives are t define the epidemilgy f rtavirus gastrenteritis, t estimate the burden f disease prir t intrductin f rtavirus vaccine, t guide the implementatin f adequate cntrl measures (including but nt limited t rtavirus vaccine) and, t evaluate the impact f the rtavirus vaccine after intrductin. Tw general appraches wuld meet the bjectives f mnitring disease trends in the cntext f assessing vaccine impact 19 : analyzing primary data surces, such as an active, gastrenteritis surveillance system; r analyzing secndary data surces, fr example natinal data n gastrenteritis hspitalizatins. Cuntries shuld cnsider the fllwing 20 : Sentinel hspital-based surveillance sites at a few selected hspitals can prvide data t dcument disease burden, baseline trends in epidemilgy, seasnality, age distributin and strain distributin. Althugh sentinel surveillance has certain limitatins in terms f ppulatin representativeness, valuable data can be btained far mre cst-effectively than establishing rtavirus surveillance natinwide. Using surveillance data t assess vaccine impact n disease burden requires cnsistent and reliable surveillance data frm befre vaccine intrductin and fr at least 3 years after vaccine intrductin t prvide an accurate estimate f disease incidence. WHO recmmends that rtavirus surveillance target all children aged 0-59 mnths admitted fr the treatment f acute (i.e. 14 days) watery gastrenteritis/diarrhea t a sentinel hspital cnducting surveillance. Excluded are children with bldy diarrhea and children transferred frm anther hspital. Rtavirus surveillance must use labratry analysis t cnfirm whether an acute diarrhea case is caused by rtavirus, as there are many ther causes f diarrhea that are nt prevented by rtavirus vaccine. As rtavirus vaccinatin becmes mre widely established in immunizatin prgrammes, new birth chrts will be immunized and prtected. Thus, a greater prprtin f severe diarrhea cases will be caused by pathgens ther than rtavirus, hwever, verall a reductin in diarrhea hspitalizatins shuld be bserved in the lngterm. 19 WHO Generic prtcl fr mnitring impact f rtavirus vaccinatin n gastrenteritis disease burden and viral strains ( and WHO Generic Prtcls (i) hspital-based surveillance t estimate the burden f rtavirus gastrenteritis in children and (ii) a cmmunitybased survey n utilizatin f healthcare services fr gastrenteritis in children (Field Test versin) ( 20 Further infrmatin can be fund n: and 36 I ntrductin f Rtavirus vaccines

38 Planning element 9 Prepare a plan t mnitr and investigate any adverse events fllwing immunizatin (AEFI) WHO recmmends that all immunizatin prgrammes have rutine AEFI mnitring in place, regardless f what vaccines are included in the natinal immunizatin schedule. All cuntries shuld at least have a system fr spntaneus reprting f AEFI and fr investigating thse that are serius. It is increasingly imprtant that any cuntry intrducing a new vaccine be able t adequately mnitr its safety, including detecting and investigating pssible reactins r AEFI. Nt being able t prmptly deal with suspected severe vaccine-related adverse events can cause cncern amngst the public, especially in cuntries with active anti-vaccine grups. This can lead t lw utilizatin f rtavirus vaccines and ptentially f ther vaccines as well, and may reduce public cnfidence in the immunizatin prgramme as a whle. Cre variables fr AEFI 21 Fr ptimal vaccine safety mnitring and meaningful analysis f AEFI data, systematic and standard cllectin f critical parameters is essential. A limited number f variables are required t prperly manage AEFI infrmatin. This includes a unique identificatin f the reprt, the primary surce f infrmatin, patient characteristics, details f the event(s) and vaccine(s) f interest and the pssibility f cllecting additinal infrmatin if needed (see example Annex 4). KEY TASKS A plan fr AEFI mnitring and, training f staff that will be respnsible fr AEFI mnitring shuld be in place befre the vaccine is intrduced 1. Develp a strategy t infrm relevant health staff that althugh the benefits utweigh the risks, a small ptential risk f intussusceptin after rtavirus vaccinatin remains. 2. Identify in-cuntry staff wh are well-infrmed abut all aspects f the vaccine and are able t discuss the vaccine benefits, risks and hw risk is being mnitred. 3. Establish channels f reprting and cmmunicatin in case f reprting f serius adverse events. 4. Develp/adapt frms and standards fr the systematic cllectin and investigatin f AEFI and train staff n their use. 5. Ensure that caregivers are adequately trained t recgnize danger signs f dehydratin r intussusceptin that need immediate medical cnsultatin. 6. Cnduct regular analysis f the rates f reprted AEFIs with supprt f the NITAG and assess the quality f the investigatins and respnse. Apart frm a lw risk f intussusceptin I ntrductin f Rtavirus vaccines

39 (abut 1 2 per infants vaccinated) the current rtavirus vaccines are cnsidered safe and well tlerated (see mre infrmatin in Annex 5). Because in the cuntries where Rtarix and RtaTeq have been first intrduced, the dses are generally being administered in accrdance with the recmmended age, data n the risk f intussusceptin fr administratin f either vaccine at lder ages are nt available. Hwever, an analysis f intussusceptin risk in infants receiving the dses at the recmmended ages suggest that bth vaccines cntinue t exhibit a gd safety prfile, but may be assciated with an increased risk f intussusceptin after the first dse f vaccine in sme ppulatins but nt in thers. The levels f risk bserved are substantially less than thse bserved with the previus vaccine, Rtashield. Based n available evidence, bth the WHO Glbal Advisry Cmmittee n Vaccine Safety (GACVS) and the WHO Strategic Advisry Grup f Experts (SAGE) n Immunizatin cncluded that the risk benefit analysis cntinues t favur early immunizatin but the previus age restrictins fr the first dse (<15 weeks) and last dse (<32 weeks) were preventing vaccinatin f many vulnerable children. By remving the age restrictins, prgrammes are nw being able t immunize children wh are currently excluded frm the benefits f rtavirus vaccines and this is likely t include sme f the children mst vulnerable t severe rtavirus disease. Many thusands mre deaths wuld be averted, but may be assciated with a small additinal increase in intussusceptin cases 22. Therefre, fr rtavirus vaccine (as fr any ther vaccine) it is necessary t establish r strengthen pstmarketing surveillance, which shuld fcus n dcumenting any intussusceptin cases. WHO has develped an E-learning curse n vaccine safety basics 23. The curse is designed t serve a brad f range f individuals invlved in vaccine safety: vaccinating health prfessinals, natinal regulatry staff, immunizatin staff, etc. Health staff must be aware f the small risk f intussusceptin after rtavirus vaccinatin and be encuraged t strengthen the detectin, reprting and investigatin f intussusceptin cases and RVGE cases t further assess risks and benefits f this vaccine. In additin, caregivers shuld be adequately cunseled t recgnize danger signs f an ill infant that requires immediate medical attentin (see Annex 5). Vaccine safety cmmunicatin 24 Immunizatin managers shuld develp vaccine safety cmmunicatin plans at cuntry level t prmte awareness f vaccine risks and benefits, understand perceptins f risk, and prepare fr managing any adverse events and cncerns abut vaccine safety prmptly. Cmmunicating abut vaccine safety is always imprtant It is essential in at least three situatins, namely: 1. explaining prperly the benefits and risks f a recmmended vaccine; 2. addressing public cncerns and upcming r persistent rumurs abut vaccine safety; 3. preparing t address vaccine safety crises if and when they ccur. Effective cmmunicatin is an nging prcess that invlves all stakehlders. Vaccine safety crises are rare and mst are nt related t prblems with vaccine prducts. Hwever, unfunded r nt, such crises have the ptential t disrupt immunizatin activities, and thereby affect public health I ntrductin f Rtavirus vaccines

40 39 I ntrductin f Rtavirus vaccines

41 Planning element Prepare an intrductin plan at natinal level and facilitate the develpment f district and 10 lcal level micr-plans fr rtavirus vaccine intrductin KEY TASKS Once a decisin has been taken t intrduce a new vaccine, the strategies and activities needed fr the vaccine intrductin have t be identified and integrated int the natinal cmprehensive multi-year plan fr immunizatin (cmyp). Guidelines have been develped t assist cuntry prgramme managers t prepare r update cmyps. 25 A cmyp Csting and Financing Tl has been develped t estimate the past csts and financing f immunizatin, and t make prjectins f future csts, future resurce requirements, future financing needs t achieve prgramme bjectives, and t analyze the crrespnding financing gaps. This tl is accmpanied by a User Guide which prvides an verview f imprtant immunizatin csting and financing cncepts, methdlgies and definitins, as well as a step-by-step instructin n hw t use the tl, including hw t analyze the data and findings 26. It is equally imprtant t encurage and supprt the develpment f detailed micrplans in all the subnatinal levels. Natinal intrductin plans are needed but are nt sufficient t ensure the successful intrductin f rtavirus vaccines. The intrductin plan shuld be accmpanied by specific micr-plans at sub-natinal level that describe all the When intrducing a new vaccine int the rutine childhd immunizatin schedule, prper planning t accmmdate the varius aspects f a new vaccine is crucial t fr a successful intrductin. 1. Seek guidance frm the Natinal Technical Advisry Grup (NITAG) n the key elements and strategic cnsideratins fr the intrductin f rtavirus vaccines. 2. Cnvene meetings f all key immunizatin actrs, including thse wrking at sub-natinal level, t identify linkages and crdinate and integrate all aspects f the rtavirus vaccine intrductin plan. 3. Prepare a detailed list f all activities required fr the successful vaccine intrductin and identify the resurce needs and ptential surces f funding fr implementatin. 4. Use all the inputs t prepare an intrductin plan. 5. Cnvene the Inter-Agency Crdinating Cmmittee (ICC) r health sectr steering cmmittee r ther relevant stakehlders meeting t discuss the plan and t take steps t incrprate the rtavirus intrductin activities int the cmyp. 6. Supprt/encurage the develpment f micr-plans fr rtavirus vaccine. intrductin at sub-natinal level 7. Wrk with sub-natinal level staff t mnitr implementatin f activities. 25 WHO- UNICEF Guidelines fr develping a cmprehensive multi-year plan (cmyp) A revised versin will be available at end f WHO-UNICEF Immunizatin Csting and Financing: A Tl and User Guide fr cmprehensive multi-year planning (cmyp). A revised versin will be available by end I ntrductin f Rtavirus vaccines

42 activities, timelines and staff respnsibilities at different levels in detail. In cuntries where there is a large prprtin f immunizatin sessins cnducted thrugh utreach r mbile teams, implementatin plans require careful cnsideratin. In the case f utreach r mbile activities, careful micr-planning is encuraged s that the apprpriate numbers f rtavirus vaccines are placed in the vaccine carrier; this will minimize unnecessary wastage at the end f the sessin. Prper sessin planning by health centers t reach their catchment ppulatins in a timely manner and the cmmitment t hld thse sessins as planned cannt be ver emphasized. Seven Planning Steps fr the develpment f cmprehensive multi-year plan (cmyp) fr immunizatin STEP 1 Situatin Analysis: Develp a situatin analysis based n a review f health system barriers, successes and prmising practices as well as identifying the strengths and weaknesses f the immunizatin system and disease cntrl initiatives. Remember t revisit the recmmendatins frm recent EPI Reviews r ther assessments (Cld Chain, Surveillance, Data Quality, etc) t infrm the analysis. STEP 2 Objectives, Milestnes and Pririty Setting: Prvide natinal gals, bjectives and strategies fr three t five years based n this situatinal analysis and n pririty setting. STEP 3 Planning Strategies: Outline the means (the hw) by which natinal immunizatin bjectives will be achieved. STEP 4: Link t Natinal Health Plans and Internatinal Gals and Targets: Link the immunizatin strategy t Natinal Health Sectr strategies, gals and targets, and t Reginal targets and the Glbal Vaccine Actin Plan (GVAP) (see: STEP 5 Set an Activity Timeline and Mnitring and Evaluatin Framewrk: Establish a timeline fr main activities and milestne achievement and develp a natinal mnitring and evaluatin framewrk fr all immunizatin cmpnents. STEP 6 Csts, Financing and Financing Gaps: In the cntext f the relevant planning cycle and the planning and budgeting cycles f the Ministry f Health, calculate csts and assess financing. Identify financing gaps, resurce mbilizatin strategies and cst benefit analysis, t re-evaluate the plan against available resurces. STEP 7 Put the cmyp int Actin: Prepare a detailed annual wrk plan and link the plan t natinal planning and budgeting cycles at natinal and sub-natinal levels f the health system. 41 I ntrductin f Rtavirus vaccines

43 Annex 1: Dcumented reductins in pneumnia and diarrhea mrbidity and mrtality with selected interventins Interventins t Prtect Exclusive breastfeeding fr 6 mnths Cntinued breastfeeding frm 6 23 mnths Adequate cmplementary feeding amng children 6 23 mnths, including adequate micrnutrient intake Vitamin A supplementatin (preventive) 23% reductin in pneumnia incidence (1); 10.5 times greater risk f death frm diarrhea and 15.1 times greater risk f death frm pneumnia if nt breastfed in first 6 mnths (2); nt breastfeeding assciated with 165% increase in diarrhea incidence in 0-5 mnth-ld infants (3); nt exclusively breastfeeding resulted in excessive risk f diarrhea incidence (RR ), prevalence (RR ), mrtality (RR ) and all-cause mrtality (RR ) in infants 0-5 mnths (4) 2.8 times greater risk f death frm diarrhea if nt breastfed (2); nt breastfeeding assciated with 32% increased diarrhea incidence in infants 6-23 mnths (3); nt breastfeeding resulted in excessive risk f diarrhea incidence (RR 1.32) in infants 6-11 mnths and prevalence (RR 2.07), mrtality (RR 2.18) and all-cause mrtality (RR 3.69) in infants 6-23 mnths (4) 6% reductin in all child deaths, including frm pneumnia and diarrhea (5) 23% reductin in all-cause mrtality (6a) and 30% reductin in diarrhea-specific mrtality (6b) in children 6-59 mnths Interventins t Prevent Vaccinatin against measles, pertussis, PCV, Hib and rtavirus Hib vaccine reduces radilgically cnfirmed pneumnia by 18% (7); 23 35% reductin in incidence f radilgical pneumnia fr PCV (1); reductin in very severe rtavirus infectin by 74% (8); ptential effectiveness f 30% fr PCV in reductin f verall childhd pneumnia mrtality (9) Preventin f HIV in children 2% reductin in all child deaths (5) Ctrimxazle prphylaxis fr HIVinfected children 33% reductin in AIDS deaths (10) Handwashing with sap 31% diarrhea risk reductin (11); 48% diarrhea risk reductin (2) Imprved sanitatin 36% diarrhea risk reductin (2) Increase quantity f water 17% diarrhea risk reductin (recgnizing a minimum quantity f at least 25 litres per persn per day is recmmended) (11) Husehld water treatment and safe 31 52% diarrhea risk reductin (greater reductins realized when strage (t ensure safe drinkingwater) used crrectly and exclusively by vulnerable ppulatins) (3, 12) Reductin in husehld air pllutin (HAP) thrugh lwer emissin stves and/r clean fuels Interventins t Treat Health facility case management fr very severe pneumnia cases and vulnerable grups such as newbrns, HIV-infected and malnurished children Increasing access t apprpriate care thrugh cmmunity-based case management f pneumnia/diarrhea (CCM) ORS Halving f HAP expsure with a chimney stve reduced severe pneumnia by 33% (13); ther evidence indicates large expsure reductins may further reduce risk (14) 29 45% reductin in case fatality (1); 6% reductin in all child deaths (5); 90% reductin in nenatal deaths due t pneumnia with hspitalbased case management (15) CCM results in 70% reductin in pneumnia mrtality (16); 35% reductin in child pneumnia mrtality (16); CCM f diarrhea with ORS and zinc reduced diarrheal deaths amng under- fives by 93% (17); 42-75% reductin in nenatal deaths due t pneumnia (15) ORS reduces diarrhea mrtality by 69% with current cverage, r 93% if 100% cverage (17) Zinc Zinc fr the treatment f diarrhea reduces diarrhea mrtality by 23% (18); 14 15% reductin in incidence f pneumnia r diarrhea (1) 42 I ntrductin f Rtavirus vaccines

44 References: 1. Niessen L et al. Cmparative impact assessment f child pneumnia interventins. Bulletin f the Wrld Health Organizatin, 2009, 87: Black RE et al. Maternal and child undernutritin: glbal and reginal expsures and health cnsequences. Lancet, 2008, 371(9608): Bhutta ZA et al. Interventins t address diarrhea and pneumnia deaths equitably: what wrks and at what csts? Lancet, 2013, in press. 4. Lamberti LM et al. Breastfeeding and the risk fr diarrhea mrbidity and mrtality. BiMed Central Public Health, 2011, 11(Supp3):S Jnes G et al. Hw many child deaths can we prevent this year? Lancet, 2003, 362: (a) Beatn, G et al. Effectiveness f vitamin A supplementatin in the cntrl f yung child mrbidity and mrtality in develping cuntries. State f the Art Series. Administrative Cmmittee n Crdinatin/ Subcmmittee n Nutritin, 1993, Geneva; and (b) Imdad, A., et al. Impact f vitamin A supplementatin n infant and childhd mrtality. BiMed Central Public Health, 2011, 11 (Suppl 3): S Thedratu E et al. The effect f Haemphilus influenza type b and pneumcccal cnjugate vaccines n childhd pneumnia incidence, severe mrbidity and mrtality. Internatinal Jurnal f Epidemilgy, 2010, 39(Suppl 1):i172- i Muns M, Fischer Walker CL, Black RE. The effect f rtavirus vaccine n diarrhea mrtality. Internatinal Jurnal f Epidemilgy, 2010, 39:i56 i Webster J et al. An evaluatin f emerging vaccines fr childhd pneumcccal pneumnia. BiMed Central Public Health, 2011, 11(Supp3):S Stver J, McKinnn R, Winfrey B. Spectrum: a mdel platfrm fr linking maternal and child survival interventins with AIDS, family planning and demgraphic prjectins. Internatinal Jurnal f Epidemilgy, 2010, 39(Suppl.1):i7- i Cairncrss S et al. Water, sanitatin and hygiene fr the preventin f diarrhea. Internatinal Jurnal f Epidemilgy, 2010, 39(Suppl.1):i193- i Clasen T et al. Interventins t imprve water quality fr preventing diarrhea: systematic review and metaanalysis. British Medical Jurnal, 2007, 334(7597): Smith KR et al. Effect f reductin in husehld air pllutin n childhd pneumnia in Guatemala (RESPIRE): a randmised cntrlled trial. Lancet, 2011, 378: Smith KR et al. Indr air pllutin frm unprcessed slid fuel use and pneumnia risk in under- 5 children: systematic review and meta- analysis. Bulletin f the Wrld Health Organizatin, 2008, 86(5): Zaidi AKM et al. Effect f case management n nenatal mrtality due t sepsis and pneumnia. BiMed Central Public Health, 2011, 11(Supp3):S Thedratu E et al. The effect f case management n childhd pneumnia mrtality in develping cuntries. Internatinal Jurnal f Epidemilgy, 2010, 39(Suppl 1):i155- i Muns MK, Walker CL, Black RE. The effect f ral rehydratin slutin and recmmended hme fluids n diarrhea mrtality. Internatinal Jurnal f Epidemilgy, 2010, 39(Suppl 1):i75- i Fischer Walker CL, Black RE. Zinc fr the treatment f diarrhea: effect n diarrhea mrbidity, mrtality and incidence f future episdes. Internatinal Jurnal f Epidemilgy, 2010, 39(Suppl 1):i63- i I ntrductin f Rtavirus vaccines

45 Annex 2: Overview f strage vlumes fr "traditinal" versus "rtavirus" vaccines "Traditinal Vaccines" Vaccine BCG Vaccine Presentatin 10-dse vial, diluent inside cld chain Dses Required (fr fully immunized child) Per dse vlume (cm3) Ttal vlume fr fully immunized child (cm3) OPV 10-dse vial Pentavalent (DTP-HepB-Hib) Measles Single-dse vial liquid vaccine dse vial, diluent inside cld chain Rtarix Pack f 1single-dse liquid vaccine Rtavirus Vaccines Rtarix Rtarix Rtarix Rtarix Pack f 10 single-dse liquid vaccine Pack f 50 single-dse liquid vaccine Pack f 1 single-dse lyphilized vaccine, packed tgether with diluent Pack f 10 single-dse lyphilized vaccine, packed tgether with diluent RtaTeq Pack f 1 single-dse liquid vaccine RtaTeq RtaTeq Pack f 10 single-dse liquid vaccine Pack f 25 single-dse liquid vaccine I ntrductin f Rtavirus vaccines

46 Annex 3: Strage vlumes fr rtavirus vaccine prducts GSK Rtarix (Liquid presentatin in ral applicatr - 2 dse schedule) Presentatin 10 ral applicatrs f single-dse per pack 1 ral applicatr f single-dse per Physical dimensins f pack (cm) Ttal vlume (cm 3 ) Length Breadth Height Length x Breadth x Height pack Strage vlume (cm 3 ) fr standard vaccinatin schedule (1) Strage vlume (cm 3 ) fr vaccinatin schedule including rtavirus vaccine(3) Ttal vlume / dse Natinal/prvincial level (2) Peripheral level Natinal/prvincial level (2) Peripheral level Ntes: (1) 1xBCG, 3xOPV, 3xDTP/HepB/Hib, 2xmeasles, 2xTT fr wmen (2) +4ºC t +8ºC strage nly (3) same as (1), with additin f 2 dses f Rtarix plus 5% wastage GSK Rtarix (Liquid presentatin in squeeze tube - 2 dse schedule) Presentatin 50 tubes f single-dse per pack 10 tubes f single-dse per pack Physical dimensins f pack (cm) Ttal vlume (cm 3 ) Length Breadth Height Length x Breadth x Height tube f singledse per pack Strage vlume (cm 3 ) fr standard vaccinatin schedule (1) Strage vlume (cm 3 ) fr vaccinatin schedule including rtavirus vaccine(3) Ttal vlume / dse Natinal/prvincial level (2) Peripheral level Natinal/prvincial level (2) Peripheral level Ntes: (1) 1xBCG, 3xOPV, 3xDTP/HepB/Hib, 2xmeasles, 2xTT fr wmen (2) +4ºC t +8ºC strage nly (3) same as (1), with additin f 2 dses f Rtarix plus 5% wastage I ntrductin f Rtavirus vaccines

47 GSK Rtarix (Lyphilized presentatin with diluents carried INSIDE cld chain - 2 dse schedule) Lyphilized 10 single-dse Presentatin pack Lyphilized 1 single-dse pack Physical dimensins f pack (cm) Length Breadth Height Ttal vlume (cm 3 ) Vlume per dse (cm 3 ) Strage vlume (cm 3 ) fr standard Natinal/prvincial level (2) vaccinatin schedule (1) Peripheral level Strage vlume (cm 3 ) fr vaccinatin Natinal/prvincial level schedule including rtavirus vaccine (3) Peripheral level Freeze-dried vaccine packed with diluents carried INSIDE the cld chain. The 10 dse cartn cntains: 2 blisters f 5 applicatrs f diluents, 1 plastic bag with ten transfer adapter + 1 bx with ten vials f vaccine Ntes: (1) 1xBCG, 3xOPV, 3xDTP/HepB/Hib, 2xmeasles, 2xTT fr wmen (2) +4ºC t +8ºC strage nly (3) same as (1), with additin f 2 dses f Rtarix plus 5% wastage Merck Rtateq - (Liquid presentatin in Squeeze Tube - 3 dse schedule) Presentatin 25 tubes f single-dse per pack 10 tubes f single-dse per pack Physical dimensins f pack (cm) Ttal vlume (cm 3 ) Length Breadth Height length x breadth x height tube f single-dse per pack Vlume per dse (cm 3 ) Strage vlume (cm 3 ) fr standard vaccinatin schedule (1) Natinal/prvincial level (2) Peripheral level Strage vlume (cm 3 ) fr vaccinatin schedule including rtavirus vaccine (3) Natinal/prvincial level (2) Peripheral level Ntes: (1) 1xBCG, 3xOPV, 3xDTP/HepB/Hib, 2xmeasles, 2xTT fr wmen (2) +4ºC t +8ºC strage nly (3) same as (1), with additin f 3 dses f RtaTeq plus 5% wastage I ntrductin f Rtavirus vaccines

48 Annex 4: Sample AEFI reprting frm using cre variables Frm can be dwnladed frm 47 I ntrductin f Rtavirus vaccines

49 Annex 5: Intussusceptin 28 What is intussusceptin? Intussusceptin is a telescping f ne segment f the bwel int itself, causing bstructin. It is a rare cnditin. The peak incidence is between 5 and 10 mnths f age, with 80% f cases befre 24 mnths f age. It is mre cmmn in males than females. Mst cases in infants are idipathic, with n recgnized triggering event r underlying structural abnrmality. There may be sme familial predispsitin. Recurrence is seen in 5-10% f nn-surgically-treated cases, usually within 6 mnths. What are the cmmn presenting symptms f intussusceptin? Intussusceptin initially causes pain, manifested as crying but ften assciated with pallr. The crying may be intermittent initially. Vmiting is the single mst cmmn symptm and signs f intestinal bstructin (distensin and absent r reduced bwel sunds) are usually present. If there is vascular cmprmise due t the bstructin, there may be intestinal bleeding (the classic red currant jelly stl) but this is ften late and/r absent. The first sign f intussusceptin in an therwise healthy infant may be sudden, lud crying caused by abdminal pain. Infants wh have abdminal pain may pull their knees t their chests when they cry. The pain f intussusceptin cmes and ges, usually every 15 t 20 minutes at first. These painful episdes last lnger and happen mre ften as time passes. Other frequent signs and symptms f intussusceptin include: Stl mixed with bld and mucus (smetimes referred t as "currant jelly" stl because f its appearance) Vmiting A lump in the abdmen Lethargy Less cmmn signs and symptms include: Diarrhea Fever Cnstipatin Sme infants have n bvius pain, dn't pass bld r have a lump in the abdmen. Sme lder children have pain but n ther symptms. Intussusceptin and the current rtavirus vaccines 29 The pathgenic mechanisms invlved in intussusceptin fllwing rtavirus vaccinatin remain prly defined. Pst-licensure surveillance shwed that the previusly marketed rtavirus vaccine, RtaShield (Wyeth- Lederle), carried an attributable risk f intussusceptin estimated at 1: recipients 30. This serius and ptentially fatal cnditin was assciated primarily with the first f the 3 ral vaccine dses and the highest attributable risk 28 Fr mre n case definitin see: Bines, J.E. et al. Acute intussusceptin in infants and children as an adverse event fllwing immunizatin: case definitin and guidelines f data cllectin, analysis, and presentatin. Vaccine: 22 (2004) ; and Bines, J.E. et al. Validatin f clinical case definitin f acute intussusceptin in infants in Viet Nam and Australia Bulletin f the Wrld Health Organizatin. July 2006, 84 (7). 29 WHO Rtavirus Vaccine Psitin Paper (January 2013) 30 Acute intussusceptin in infants and yung children (WHO/V&B/.02.19). Geneva, Wrld Health Organizatin, Available at accessed January I ntrductin f Rtavirus vaccines

50 was fund in infants >3 mnths f age receiving the vaccine. Radmized cntrl trials (RCTs) cnducted s far have lacked pwer t rule ut very small relative risks f assciatin between Rtarix r RtaTeq and intussusceptin in narrw risk windws, fr example the 1-7 day perid after dse 1. Hwever, n increased risk f intussusceptin was detected with either vaccine in tw RCTs, each f which included apprximately infants ( received rtavirus vaccine) and designed t detect a risk similar t that seen with Rtashield. Using self-cntrlled case-series and case-cntrl methds the ptential assciatin between Rtarix and intussusceptin was investigated after rutine immunizatin f infants in Mexic and Brazil. The study included 615 intussusceptin case patients (285 in Mexic and 330 in Brazil) and 2,050 cntrls. An increased risk f intussusceptin 1 7 days after the first dse f Rtarix was identified amng infants in Mexic using bth the selfcntrlled case-series methd (incidence rati, 5.3; 95% CI: ) and the case-cntrl methd (dds rati, 5.8; 95% CI: ). Amng infants in Brazil n significant risk was fund after the first dse, but an increased risk by a factr f 1.9 t 2.6 was seen 1 7 days after the secnd dse. A cmbined annual excess f 96 cases f intussusceptin in Mexic (apprximately 1 per infants) and in Brazil (apprximately 1 per infants) and f 5 deaths due t intussusceptin was attributable t Rtarix in this analysis. A prspective, active surveillance study fr intussusceptin in infants fllwing Rtarix vaccinatin was cnducted in Mexic during the perid The relative incidence f intussusceptin within 31 days f vaccinatin was 1.8 (95% CI: ; p=0.001) pst dse 1 and 1.1 (95% CI: ; p=0.8) pst-dse 2. The relative incidence f intussusceptin within 7 days f vaccinatin was 6.5 pst-dse 1 (95% CI: ; p<0.001) and 1.3 pstdse 2 (95% CI: ; p=0.3). The attributable risk f intussusceptin within 7 days f vaccine dse 1 was estimated at 3 t 4 additinal cases f intussusceptin per vaccinated infants. In Australia, an excess f bserved cmpared t expected cases f intussusceptin was reprted fr bth Rtarix and RtaTeq amng children 1 3 mnths f age. With Rtarix, the relative risk was 3.5 (95% CI: ) 1 7 days after the first dse and 1.5 (95% CI: ) 1 21 days after the first dse. The crrespnding figures fr RtaTeq were 5.3 (95% CI: ) and 3.5 (95% (CI: ). Tw large chrt studies with active fllw-up assessed the risk f intussusceptin fllwing receipt f RtaTeq in the USA. In ne cvering the perid , a ttal f RtaTeq dses, including first dses, were administered t infants 4 34 weeks f age. Cmparing the incidence f intussusceptin between rtavirus vaccine recipients and similarly aged recipients f ther infant vaccines, n statistically significant increased risk f intussusceptin with RtaTeq was bserved fr either cmparisn grup fllwing any dse in either the 1 7 day r 1 30 day risk windw. The ther US study, which cmpared the risk f intussusceptin between RtaTeq recipients and DTaP recipients fund 6 and 5 cnfirmed cases f intussusceptin, respectively, within 30 days fllwing either dse. The relative risk f intussusceptin was 0.8 (95% CI: ). Thus, in sme but nt all settings, pst-marketing surveillance f bth currently available rtavirus vaccines has detected a small increased risk f intussusceptin (abut 1 2/ infants vaccinated) shrtly after the first dse. Where present, this risk is 5 10 times lwer than that bserved with the previusly licensed RtaShield, and the benefits f rtavirus vaccinatin against severe diarrhea and death frm rtavirus infectin far exceeds the risk f intussusceptin. 49 I ntrductin f Rtavirus vaccines

51 Annex 6: Key Advcacy & Cmmunicatins Messages Related t Rtavirus Vaccines 1. WHO recmmends including rtavirus vaccine in all natinal immunizatin prgrammes. 2. Mre than 85% f rtavirus deaths ccur in high mrtality settings. Studies demnstrate that apprximately 30-60% f rtavirus gastrenteritis (RVGE) deaths can be prevented by use f rtavirus vaccine Because there are many micrbilgical causes f diarrheal disease, a cmprehensive apprach t diarrheal disease cntrl shuld be implemented tgether with rtavirus vaccine intrductin. This cmprehensive apprach strategy, shuld include exclusive breastfeeding fr 6 mnths, vitamin A supplementatin, safe drinking water, hygiene (including hand washing with sap), and sanitatin; treatment with lw-smlarity ral rehydratin slutin (ORS), zinc supplements, and cntinued feeding. 4. WHO, UNICEF, and ther partners are wrking tgether in a new accelerated and integrated apprach t cmbat rtavirus diarrhea and pneumnia, the tw leading childkillers, which tgether accunt fr mre than 29% f all under five child deaths every year, the majrity f which are in the develping wrld. 5. Key messages abut rtavirus vaccine use (all messages apply t bth Rtarix and RtaTeq ) KEY MESSAGES Diarrheal disease remains a serius public health issue fr children acrss the glbe. In develping cuntries, diarrhea is a majr cause f under-5 year ld mrtality, accunting fr up t 11% f all childhd deaths. These deaths are preventable. Wrldwide, it is estimated that arund 40% f all pediatric hspitalizatins fr diarrhea are attributable t rtavirus infectins. Vaccinatin against rtavirus is an effective way t prevent this deadly disease. Rtavirus infects nearly every child by the age f 3-5 years. In develping cuntries, first rtavirus infectins usually ccur between by 26 weeks f age, and nearly 80% ccur amng infants <1 year ld, althugh there are sme differences amng cuntries In 2008, rtavirus was estimated t have caused 453,000 deaths wrldwide amng infants and very yung children, with 90% f these deaths ccurring in Africa and Asia alne. Given that there are many causes f diarrheal disease, the rtavirus vaccine must be part f a cmprehensive cntrl strategy, including exclusive breastfeeding fr 6 mnths, vitamin A supplementatin, safe drinking water, hygiene (especially hand-washing with sap) and sanitatin, and treatment with ORS, zinc supplementatin, and cntinued feeding. Rtavirus is resilient and traditinal hygiene measures that might prevent ther sanitatin-related illnesses are nt sufficient t limit its impact, hence the cmparable rate f infectin glbally. 31 Sandersn, C. et al. 2011, Glbal review f rtavirus mrbidity and mrtality data by age and regin. Reprt t WHO/IVR. (accessed July 19, 2013). 50 I ntrductin f Rtavirus vaccines

52 Annex 7: Frequently Asked Questins fr Health Wrkers What is rtavirus disease? Rtavirus is the mst cmmn cause f severe diarrhea in infants and yung children wrldwide. It can lead t severe dehydratin and death. WHO estimates (2008) that apprximately 453,000 children died frm rtavirus infectin and many mre were hspitalized. Wh can get rtavirus infectin? Nearly all children in the wrld, regardless f where they live, will suffer at least ne rtavirus infectin in the first five years f life. Hwever, the vast majrity f rtavirus deaths ccur in develping cuntries, where prmpt medical care may be ut f reach. Hw is rtavirus spread? Rtaviruses are easily spread primarily by the faecal-ral rute, directly frm persn-tpersn, r indirectly via cntaminated fmites. What are the symptms f rtavirus disease? Clinical illness frm rtavirus infectin ranges frm mild watery diarrhea f limited duratin, t severe diarrhea with vmiting that may result in dehydratin and death if apprpriate treatment is nt available. Fllwing an incubatin perid f 1 2 days, the illness can begin abruptly, and vmiting ften precedes the nset f diarrhea. Up t ne-third f patients may have a temperature greater than 39 C. Gastrintestinal symptms generally reslve within 3 7 days. Children with rtaviruses ften suffer frequent vmiting that may smetimes make it difficult t administer ral rehydratin slutin (ORS) at hme, and medical care is required. It is nt pssible t distinguish rtavirus frm ther causes f gastrenteritis n clinical grunds alne, and a labratry test is required t cnfirm the diagnsis. The first infectin is usually the mst severe; later infectins may be milder r asymptmatic due t previus acquired immunity. Hw can rtavirus infectin be prevented? Imprvements in sanitatin, safe water supply, prmtin f exclusive breastfeeding fr 6 mnths and imprvement in children s nutritin, including vitamin A supplementatin are imprtant t prevent diarrheal disease. Hwever, such interventins have limited benefits in preventing rtavirus infectin. Childhd rtavirus vaccinatin is the best methd t prevent severe disease and rtavirus deaths. Is there a vaccine against rtavirus disease? Tw rally-administered, live, attenuated vaccines against rtavirus infectin have been demnstrated t be safe and highly efficacius in large-scale clinical trials; Rtarix manufactured by GlaxSmithKline Bilgicals, and RtaTeq, manufactured by Merck and C. They prvide gd prtectin against severe rtavirus-related diarrhea in yung children, but they d nt prvide 100% prtectin against the infectin. Bth vaccines are prequalified by WHO, and have already been intrduced int the rutine childhd immunizatin in many cuntries. The current rtavirus vaccines differ in antigen cmpsitin and immunizatin schedule, but they are cnsidered equally safe and efficacius by WHO. D the lcally prevalent strains f rtavirus influence the chice f vaccine? Available evidence shws that bth vaccines prvide crss-prtectin against strains nt cntained in the vaccine. The efficacy and effectiveness f either vaccine des nt seem t be affected by the strains f rtavirus prevalent in the ppulatin.

53 Wh shuld get the rtavirus vaccine? Generally, all children shuld receive rtavirus vaccine in infancy with their ther childhd vaccines. Hw many dses are needed? When shuld they be given? Rtavirus vaccines can be administered frm the age f 6 weeks f age and given simultaneusly with DTP/penta vaccines. Rtarix shuld be administered rally in a 2-dse schedule at the time f DPT1/penta1 and DPT2/penta2 with and interval f at least 4 weeks between dses. RtaTeq shuld be administered rally in a 3-dse schedule at the time f the DTP1/penta1, DTP2/penta2, and DTP3/penta3 cntacts, with an interval f at least 4 weeks between dses. Rtavirus vaccines must never be injected. Can the rtavirus vaccines be c-administered with ther vaccines? Rtavirus vaccinatins can be administered simultaneusly with ther vaccines in the infant immunizatin prgramme. Is there any reasn why a child shuld nt be given rtavirus vaccine? Severe allergic reactin (e.g. anaphylaxis) after a previus dse, and severe immundeficiency including severe cmbined immun-deficiency (SCID), are cntraindicatins fr rtavirus vaccinatin. What are the precautins t rtavirus vaccine administratin? Precautins are necessary if there is a histry f intussusceptin r intestinal malfrmatins, chrnic gastrintestinal disease, and severe acute illness. Vaccinatin shuld be pstpned in case f nging acute gastrenteritis r fever with mderate t severe illness until the child recvers. The presence f minr infectins, hwever, is nt a cntraindicatin fr vaccinatin. What are the pssible adverse events fllwing rtavirus vaccine? Apart frm a lw risk f intussusceptin (abut 1 2 per infants vaccinated) the current rtavirus vaccines are cnsidered safe and well tlerated. Cuntries shuld develp a strategy t infrm relevant health staff that althugh the benefits utweigh the risks, a small ptential risk f intussusceptin after rtavirus vaccinatin remains. Cuntries shuld als ensure that caregivers are adequately cunseled t recgnize danger signs f dehydratin r intussusceptin that need immediate medical attentin. Prper planning and training f staff t cnduct pharmacvigilance shuld take place befre the vaccine is intrduced. Given the backgrund rate f natural intussusceptin and the large number f children included in natinal immunizatin prgrammes, intussusceptin cases are expected t ccur by chance alne fllwing rtavirus vaccinatin. It is imprtant t establish the baseline incidence f intussusceptin at sentinel sites and t use epidemilgical studies, such as the self-cntrlled case series methd, t assess the safety f rtavirus vaccines. Hw shuld the rtavirus vaccines be stred? Rtavirus vaccines shuld be stred between 2 C and 8 C. This vaccine shuld nt be frzen. 52 I ntrductin f Rtavirus vaccines

54 Annex 8: Rtavirus vaccines: A Pcket Guide fr Health Wrkers Annex 8 Rtavirus vaccines: A Pcket Guide fr Health Wrkers UPDATE I ntrductin f Rtavirus vaccines

55 Frewrd Cuntries are intrducing the rtavirus vaccine. This Pcket Guide is a hands-n practical dcument that is part f the learning material fr rtavirus vaccine intrductin training. The Pcket Guide is structured by tpic. Each tpic is addressed with shrt descriptins, illustratins, and key messages. This Pcket Guide prvides an illustrative framewrk fr users and is t be adapted t lcal cnditins. 54 I ntrductin f Rtavirus vaccines

56 Table f Cntents Intrductin t rtavirus disease 55 What can be dne t prevent diarrheal disease? 57 Rtavirus vaccine 58 Rtavirus vaccine strage 60 Vaccine eligibility 61 Vaccine cntraindicatins 62 Vaccine preparatin 63 Vaccine recrding 66 Arranging fr a return visit 67 Tracking infants fr rtavirus vaccine 69 Key messages 70 Intussusceptin 70 Mnitring AEFIs 71 Cmmunicating with caretakers 73 Advice n what is given 74 Cmmunicating abut side effects and hw t respnd 75 Intrductin t rtavirus disease Rtavirus disease is a diarrheal disease caused by a virus called rtavirus. The name rtavirus cmes frm the wheel-like appearance f the virus under the micrscpe. Rtavirus is the mst cmmn cause f severe diarrheal disease in infants and yung children wrldwide. 55 I ntrductin f Rtavirus vaccines

57 Wh is at mst risk? Infants after the age f 3 mnths Lw t n immunity Vulnerable t dehydratin Older children if they are immuncmprmised What are the signs and symptms f rtavirus disease? Fever Vmiting Watery diarrhea Abdminal pain may als ccur. Diarrhea usually stps after 3 t 7 days. The virus damages the cells f the small intestine s that the bdy cannt absrb water and nutrients. Children may lse interest in eating and drinking and becme dehydrated frm lss f fluids. Vmiting is especially dangerus because it is difficult t replace fluids in yung children wh are vmiting frequently. Yung children can becme dehydrated, requiring urgent treatment. Hw des rtavirus spread? Rtavirus is very cntagius, and spreads easily frm children wh are already infected t ther children and smetimes adults. Large amunts f rtavirus are excreted in the stl f infected persns and the virus can be easily spread via cntaminated hands and bjects, such as tys. This is knwn as a fecal-ral rute f transmissin. Rtavirus is nt the nly cause f diarrhea, several ther agents may als cause diarrhea. Cnfirmatin f rtavirus diarrheal illness requires labratry testing. Strains f rtavirus may be further characterized by special testing with enzyme immunassay r plymerase chain reactin. Such testing is nt cmmnly available r necessary. 56 I ntrductin f Rtavirus vaccines

58 What can be dne t prevent diarrheal disease? High level f rtavirus mrbidity cntinues t ccur in the wrld Rtavirus vaccine prtects against ne cause f diarrhea, but nt all causes. Therefre, the use f rtavirus vaccine needs t be part f a cmprehensive strategy t cntrl diarrheal diseases with the scaling up f bth preventin (prmtin f early and exclusive breastfeeding fr six mnths, vitamin A supplementatin, safe drinking water, hygiene, especially hand-washing with sap, and sanitatin) and treatment packages (ORS, zinc, and cntinued feeding). 57 I ntrductin f Rtavirus vaccines

59 Rtavirus vaccine Tw ral rtavirus vaccines are marketed internatinally : the mnvalent (RV1) Rtarix (GlaxSmithKline Bilgicals, Rixensart, Belgium) the pentavalent (RV5) RtaTeq (Merck & C. Inc., West Pint, PA, USA). Currently available efficacy and safety data supprt selectin f either f the tw vaccines fr natinal use. Althugh bth rtavirus vaccines are efficacius, data shw that their efficacy is higher in settings with lw mrtality in children under five years f age (vaccine efficacy ~ 90%) than, in settings with high mrtality in children under five years f age (vaccine efficacy~ 60%). Because the incidence f rtavirus disease is significantly higher in high child mrtality settings, the number f severe disease and deaths averted by rtavirus vaccines in these settings is likely t be greater than in lw mrtality settings, despite the lwer vaccine efficacy. It is imprtant t bear in mind that rtavirus vaccine will nt prevent r prtect diarrhea r vmiting caused by ther germs, but it is very effective at preventing diarrhea and vmiting caused by rtavirus. This means that even when children are fully immunized against rtavirus, they may still get diarrhea caused by ther agents. 58 I ntrductin f Rtavirus vaccines

60 GSK Rtarix - mnvalent, human strain, live, attenuated, ral rtavirus vaccine Vaccine type RV1 is a live vaccine Rute f administratin Presentatin Vaccine picture Oral Liquid Rtarix in ral applicatr (single dse) Liquid Rtarix in squeezable plyethylene tube (single dse) Lyphilized Rtarix vaccine recnstituted with CaCO3 buffer (single dse) Administratin Administered rally using the applicatr Administered rally using the tube Administered rally using the applicatr Vaccine Vial Mnitr (VVM) Packaging Surce Has VVM 14 Has VVM 14 Has VVM 14 1 and 10 ral applicatrs per pack. GSK Bilgicals 1,10, r 50 tubes f single-dse per pack 1 and 10 single-dses per pack. Merck RtaTeq - pentavalent, human-bvine reassrtant strain, live, attenuated, ral, rtavirus vaccine Vaccine type RV5 is a live vaccine Rute f Oral administratin Presentatin One presentatin: ral squeezable tube (single dse) Vaccine picture Administratin Vaccine Vial Mnitr (VVM) Packaging Surce Administered rally using the squeeze tube Des nt have a VVM Available in 1,10, 25 tubes f single-dse per pack Significant cld chain vlume implicatins Merck & C. 59 I ntrductin f Rtavirus vaccines

61 Rtavirus vaccine strage The rtavirus vaccine shuld be stred in a refrigeratr. D nt put rtavirus vaccine in the freezer. If the vaccines are frzen, they lse their ptency and n lnger prvide prtectin against the disease. Vaccines with early expiratin dates (and/r VVM in stage 2 (r nearing stage 2) if it has a VVM) shuld be kept in the frnt f the refrigeratr fr first use. Gd temperature cntrl during the strage and transprt f vaccines is critical t ensure the ptency and safety f vaccines. Rtavirus vaccines must be stred between +2 C and +8 C. Fr rtavirus vaccine furnished withut VVMs (RtaTeq ), it is highly recmmended t use cntinuus temperature mnitring devices t stre and transprt vaccines under cld chain cnditins as specified by the manufacturer. Any break in the cld chain shuld be recrded and immediately reprted thrugh the supervisry channels. VVMs attached t ther vaccines cannt be used as a prxy t determine the cumulative level f heat expsure experienced by RtaTeq. In situatins where cntinuus temperature mnitring devices are nt available, the fllwing is recmmended: Discard unpened tubes immediately if there is a cmplete and sustained rupture in the cld chain and the ambient temperature exceeds 25 C; Discard unpened tubes if there is a temprary rupture in the cld chain and the vaccine is expsed t temperatures between 9 t 25 C fr mre than 36 cnsecutive hurs; Discard unpened vaccine tubes at the end f utreach r mbile sessins if there is n assurance that the cld chain was maintained. 60 I ntrductin f Rtavirus vaccines

62 Vaccine eligibility Immunizatin schedule fr Rtarix (RV1) vaccine Immunizatin schedule fr RtaTeq (RV5) vaccine Rtarix shuld be administered rally in a 2- dse schedule at the time f DTP/penta1 and DTP/penta2 with and interval f at least 4 weeks between dses. The first dse f rtavirus vaccine shuld be given at 6 weeks f age r sn thereafter. RtaTeq shuld be administered rally in a 3- dse schedule at the time f the DTP/penta1, DTP/penta2, and DTP/penta3 cntacts, with an interval f at least 4 weeks between dses. The first dse f rtavirus vaccine shuld be given at 6 weeks f age r sn thereafter. On-time vaccinatin is very imprtant fr rtavirus vaccine. Hwever, if a child is late fr vaccinatin: He/she can get rtavirus vaccine He/she can get all ther vaccines in the schedule Because f the typical age distributin f rtavirus gastr-enteritis, rtavirus vaccinatin f children >24 mnths f age is nt recmmended. Prematurely brn infants shuld fllw the vaccinatin schedules recmmended fr their chrnlgical age. Rtavirus vaccinatins can be administered simultaneusly with ther vaccines in the infant immunizatin prgramme. Early vaccinatin (first dse t be given as sn as pssible after 6 weeks f age) is encuraged but infants can receive rtavirus vaccine tgether with DTP/penta regardless f the time f vaccinatin. Nevertheless, as rtavirus is a disease that affects yung infants, the intrductin f rtavirus vaccine shuld be accmpanied by measures t ensure high vaccinatin cverage and timely administratin f each dse in rder t maximize the benefits f the vaccine. 61 I ntrductin f Rtavirus vaccines

63 Vaccine cntraindicatins Cntraindicatins Hypersensitivity after previus administratin f rtavirus vaccines Severe immundeficiency Precautins are necessary if there is a histry f intussusceptin r intestinal malfrmatins, chrnic gastrintestinal disease and severe acute illness. Administratin f rtavirus vaccine shuld be pstpned in subjects suffering frm n-ging acute diarrhea r vmiting and in need f rehydratin therapy, r fever with mderate t severe illness. Nte that mild illness such as an upper respiratry tract infectin is nt a cntraindicatin. 62 I ntrductin f Rtavirus vaccines

64 Vaccine preparatin 1. ROTARIX Befre preparing rtavirus vaccine Befre administering the vaccine, yu need t verify and interpret the Vaccine Vial Mnitr (VVM) and always check the expiratin date marked n the tube cap. Prepare fr vaccinatin Step 1: Pull ff the cap frm the tube. Clear the fluid frm the upper part f the tube by tapping the tube. Step 2: Turn the cap upside-dwn and place the cap vertically nt the tip seal. Insert the tip seal int the small hle in the tp f the cap. 63 I ntrductin f Rtavirus vaccines

65 Administer the vaccine The child shuld be seated in a semi reclining psitin (i.e. nrmal feeding psitin) t take the vaccine rally. Befre administratin f the vaccine, make a final visual inspectin t ensure that the tip has nt fallen inside the tube Step 1: Open the muth f the child by gently pressing the cheeks. Step 2: Put the tube twards the inner cheek. Make every effrt t aim the tube cntaining the vaccine dwn ne side and tward the back f the child's muth. D nt put the tube t far back in the muth. Never place the tube int the center f the muth t prevent the risk f chking. Step 3: Administer the vaccine slwly by pressing the tube. Prevent spitting by administering the vaccine in small prtins slwly. 2. ROTATEQ Step 4: Make sure the child is swallwing the vaccine. Hld the cheeks tgether and strke him/her under the chin t help with swallwing. A replacement dse maybe given if the child spits part f the vaccine. Befre preparing rtavirus vaccine Befre administering the vaccine, yu need t always check the expiratin date marked n the tube cap. 64 I ntrductin f Rtavirus vaccines

66 Administer the vaccine 65 I ntrductin f Rtavirus vaccines

67 The child shuld be seated in a semi reclining psitin (i.e. nrmal feeding psitin) t take the vaccine rally. Befre administratin f the vaccine, make a final visual inspectin t ensure that the tip has nt fallen inside the tube. Step 1: Open the muth f the child by gently pressing the cheeks. Step 2: Put the tube twards the inner cheek. Make every effrt t aim the tube cntaining the vaccine dwn ne side and tward the back f the child's muth. D nt put the tube t far back in the muth. Never place the tube int the center f the muth. Step 3: Administer the vaccine slwly by pressing the tube. Prevent spitting by administering the vaccine in small prtins slwly. Step 4: Make sure the child is swallwing the vaccine. Hld the cheeks tgether and strke him/her under the chin t help with swallwing. A replacement dse is nt necessary if the child spits part f the vaccine. Vaccine recrding 66 I ntrductin f Rtavirus vaccines

68 Immunizatin card Each time a vaccine is administered, cmplete the vaccinatin card utlining which vaccines have been given. Yu shuld als nte the date f the next appintment n the immunizatin card and remind the caretaker t return n that date with the card. Immunizatin card use Parents shuld be reminded t bring the immunizatin card at each visit. Nte that the immunizatin card has been updated t include the rtavirus vaccine dses, and the generic abbreviatin fr rtavirus vaccine is "Rta." Use this abbreviatin when recrding the vaccine being administered. Tally sheet Tally sheets have been updated t reflect the inclusin f rtavirus vaccine in the natinal immunizatin prgram. Keep a tally f each vaccine dse given. At the end f an immunizatin sessin, cunt the tally sheets t identify the ttal number f vaccinatins given (fr each dse). If yu have ld tally sheets, include a line fr Rta1 and Rta2 and Rta3, as apprpriate (depending n which rtavirus vaccine was intrduced in yur cuntry). Mnthly reprt Reprting frms have been updated t reflect the inclusin f rtavirus vaccine in the natinal immunizatin prgram. Reprt rtavirus vaccine dses administered each mnth, alng with ther vaccine dses. If yu have ld reprting frms, add lines t reprt Rta1 and Rta2 and Rta3 as apprpriate. Use tally sheets t prepare mnthly reprts t send t supervisrs. Arranging fr a return visit Make an appintment fr the next dse f rtavirus vaccine and ther vaccines accrding t the immunizatin schedule. Ensure that a minimum gap f 4 weeks is maintained. Ensure that there is a sessin n the given date (n public hliday, weekend, etc.). 67 I ntrductin f Rtavirus vaccines

69 Write the date f the next visit n the immunizatin card and remind the caretaker t cme n the specified date and t bring the card. 68 I ntrductin f Rtavirus vaccines

70 Tracking infants fr rtavirus vaccine The first dse f rtavirus vaccine can be given t infants frm 6 weeks f age. In rder t prtect infants frm catching the disease, rtavirus vaccine needs t be given as sn as pssible. Use vlunteers t infrm and mtivate parents f newbrns t bring their children fr vaccinatin n time. Parents f infants wh are due fr vaccinatin, but have nt yet cme t the health center, shuld be reminded and fllwed up with. A cpy f the immunizatin card may be filed under the mnth the infant shuld return fr the next dse f rtavirus vaccine. Fr example, if an infant receives pentavalent vaccine and rtavirus vaccine in January, place a cpy f the card in the February sectin. Every mnth, review the reminder cards and fllw up with thse wh did nt attend when due. Invlve cmmunity vlunteers t bring children wh are eligible fr the secnd dse. Als explain t the vlunteers why it is imprtant t bring children back fr the subsequent dses at the recmmended ages. Mnitr uptake f rtavirus vaccine Year : 2013 Use a wall mnitring chart t track the number f infants wh received each f the recmmended dses f rtavirus vaccine. If the gap between each dse f rtavirus vaccine is large, this means that several children received the first dse but nt the secnd r the third dse, as apprpriate. Thus, fllw-up systems need t be strengthened. A big gap between mnthly targets and infants getting Rta1 means newbrns need t be fllwed up with regularly. 69 I ntrductin f Rtavirus vaccines

71 KEY MESSAGES The infant must receive all dses f the vaccine t be fully prtected and he/she must receive the dses as sn as pssible frm 6 weeks f age. Because rtavirus disease affects yung infants the mst, it is imprtant that they get vaccinated n time. The caretaker must bring the infant back t the health center as advised r make effrts t attend the next scheduled utreach/mbile sessin visit. Health wrkers shuld clearly cmmunicate the time, date and lcatin f the next utreach/mbile visit, r the next scheduled immunizatin sessin at the fixed-site, and encurage the caretakers' return. The rtavirus vaccine prtects the infant against ne cause f diarrhea, but nt all causes. Preventin f childhd diarrheal diseases als requires early and exclusive breastfeeding fr six mnths, vitamin A supplementatin, safe drinking water, hygiene (especially handwashing with sap) and sanitatin. If the infant suffers frm severe diarrhea, take him r her t the health center r cmmunity health wrker immediately t get treatment (e.g., lw-smlarity ral rehydratin slutin (ORS), zinc tablets, and cntinued feeding). Intussusceptin Intussusceptin (IS) is a rare type f bwel bstructin that ccurs when ne prtin f the bwel slides int an immediately adjacent segment (als knwn as telescping r prlapse). Symptms f IS include stmach pain with severe crying (which may be brief); several episdes f vmiting; bld in the stl; weakness, r irritability. 70 I ntrductin f Rtavirus vaccines

72 Intussusceptin was fund t be a rare but significant side effect f the first generatin rtavirus vaccine (RtaShield ) that was available in the United States in Bth Rtarix and RtaTeq vaccines were tested in large studies designed t exclude a risk f intussusceptin similar t RtaShield. In these studies n increased risk f intussusceptin bserved. As even large pre-registratin safety studies cannt detect rare events, pst-marketing studies have been undertaken in a number f cuntries. Apart frm a lw risk f intussusceptin (abut 1 2 per infants vaccinated) the current rtavirus vaccines are cnsidered safe and well tlerated. Mnitring AEFIs An adverse event fllwing immunizatin (AEFI) is a medical incident that takes place after an immunizatin, causes cncern, and is believed t be caused by the immunizatin. The safety prfile f the rtavirus vaccines currently available is gd. Mst infants wh get the rtavirus vaccine d nt experience any side effects. Reprt adverse events Health wrkers, wh administer the vaccine, shuld ask the parents t immediately reprt any reactin that may be related t the vaccine. Reprt the identified AEFI thrugh the existing AEFI reprting systems established by natinal immunizatin prgrammes. Other prblems related t the vaccines, such as administering the vaccines t infants wh shuld nt be vaccinated, r errrs in vaccine administratin, shuld als be reprted. Cre variables fr AEFI Fr ptimal vaccine safety mnitring and meaningful analysis f Adverse Event Fllwing Immunizatin (AEFI) data, systematic and standard cllectin f critical parameters is essential This includes: a unique identificatin f the reprt, 71 I ntrductin f Rtavirus vaccines

73 the primary surce f infrmatin, patient characteristics, details f the event(s) and vaccine(s) f interest and the pssibility f cllecting additinal infrmatin if needed. Imprtant: Reassure the caretaker Admit uncertainty, investigate fully, and keep the cmmunity infrmed 72 I ntrductin f Rtavirus vaccines