Real-time safety surveillance of seasonal influenza vaccines in children, Australia, 2015

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1 Rpid communictions Rel-time sfety surveillnce of sesonl influenz vccines in children, Austrli, 2015 A Pillsury 1, P Cshmn 2 3, A Lee 4, A Regn 5 6, D Westphl 5 7 8, T Snelling 7 9, C Blyth , N Crwford , N Wood 1 14, K Mcrtney , on ehlf of the AusVxSfety, surveillnce tem Ntionl Centre for Immunistion Reserch nd Surveillnce, The Children s Hospitl t Westmed, NSW, Austrli 2. Hunter New Englnd Locl Helth District, NSW, Austrli 3. The University of Newcstle, NSW, Austrli 4. Illwrr Medicl Centre, WA, Austrli 5. Communicle Disese Control Directorte, Western Austrli Deprtment of Helth, WA, Austrli 6. School of Pthology nd Lortory Medicine, University of Western Austrli, WA, Austrli 7. Wesfrmers Centre of Vccines nd Infectious Diseses, Telethon Kids Institute, University of Western Austrli, WA, Austrli 8. Ntionl Centre for Epidemiology nd Popultion Helth, Reserch School of Popultion Helth, The Austrlin Ntionl University, ACT, Austrli 9. Princess Mrgret Hospitl, WA, Austrli 10. University of Western Austrli School of Peditrics nd Child Helth, Princess Mrgret Hospitl, WA, Austrli 11. Deprtment of Generl Medicine, Royl Children s Hospitl, Victori, Austrli 12. SAEFVIC, Murdoch Childrens Reserch Institute, Victori, Austrli 13. Deprtment of Peditrics, The University of Melourne, Victori, Austrli 14. Discipline of Peditrics nd Child Helth, University of Sydney, NSW, Austrli 15. Deprtment of Microiology nd Infectious Diseses, The Children s Hospitl t Westmed, NSW, Austrli 16. The memers of the group re listed t the end of the rticle. Correspondence: Alexis Pillsury (lexis.pillsury@helth.nsw.gov.u) Cittion style for this rticle: Pillsury A, Cshmn P, Lee A, Regn A, Westphl D, Snelling T, Blyth C, Crwford N, Wood N, Mcrtney K. Rel-time sfety surveillnce of sesonl influenz vccines in children, Austrli, Euro Surveill. 2015;20(43):pii= DOI: ;20(34):pii= DOI: Article sumitted on 14 Octoer 2015 / ccepted on 29 Octoer 2015 / pulished on 29 Octoer 2015 Incresed ferile rections in Austrlin children from one influenz vccine rnd in 2010 diminished confidence in influenz immunistion, highlighting the need for improved vccine sfety surveillnce. AusVxSfety, ntionl vccine sfety surveillnce system collected dverse events in young children for 2015 influenz vccine rnds in rel time through prent/crer reports vi SMS/emil. Weekly cumultive dt on 3,340 children demonstrted low rtes of fever (4.4%) nd medicl ttendnce (1.1%). Fever ws more frequent with concomitnt vccintion. In 2014, multi-jurisdictionl ntionl system, AusVxSfety, ws estlished to undertke enhnced influenz vccine sfety surveillnce nd report reltime dverse events in children ged six months to four yers. This collortive system ws funded y the Austrlin Government Deprtment of Helth. Surveillnce (n = 782 children) demonstrted the sfety of 2014 sesonl influenz vccines in mtter of weeks, lthough most children received one vccine rnd (Vxigrip, Snofi Psteur; 86.2%; n = 674 children) [1,2]. Expnsion of the progrmme in 2015 to incorporte new dt mngement pltform nd more prticipting generl prctice (GP) sites (GPs provide more thn 70% of vccines given ntionlly [3]) hs enled reporting of the sfety of 2015 southern hemisphere trivlent influenz vccines for thousnds of children receiving multiple mnufcturers vccines. Here we report the results of our surveillnce conducted during the 2015 Austrlin influenz seson. The AusVxSfety vccine sfety surveillnce system In Austrli (popultion 23 million [4]), influenz vccintion is funded under the Ntionl Immunistion Progrm for children ged six months to four yers who hve medicl conditions pre-disposing them to complictions nd/or for Indigenous children. Only one stte, Western Austrli (WA), hs funded influenz vccintion for this ge group since For the purposes of AusVxSfety surveillnce, children ged six months to four yers receiving sesonl influenz vccine from prticipting GP sites (n = 54), hospitls (n = 6), pulic clinics (n = 2) nd primry helthcre providers such s Aoriginl Medicl Services (n = 7) in four sttes (New South Wles (NSW), Victori, South Austrli nd WA) were eligile for inclusion. Prent/ crer-reported dverse events in children were solicited within three dys of vccintion using two computersed dt mngement pltforms, Vxtrcker [5] nd SmrtVx [6]. Both systems sent utomted SMS messges (nd/or emils for Vxtrcker) nd received prent/crer-completed questionnire responses vi reply SMS with URL link to smrtphone survey (SmrtVx) 1

2 Figure AusVxSfety prticipnts with nd without postvccine rection, y week of vccintion, nd cumultive percentge of prticipnts, Austrli, 1 April 31 August 2015 (n = 3,340) Numer of cses Surveillnce week Any dverse rection (n=385) No rection (n=2,955) Surveillnce Week 1 included ll prticipnts vccinted prior to the officil rollout of the influenz vccine for the 2015 seson (20 April 2015) nd cptured children vccinted from 1 to 19 April After tht, ech surveillnce week consisted of seven dys, with Week 2 including April, etc. Week 20 included eight dys (24 31 August 2015). or we-sed survey (Vxtrcker). Demogrphic detils were otined, s well s informtion regrding vccine rnd, medicl conditions, concomitnt vccines, rections nd helthcre consulttions required fter vccintion (including follow-up visit to GP, emergency deprtment (ED) or hospitlistion). Serious dverse events (SAE) were ctegorised ccording to predefined criteri, which included ny untowrd medicl event tht resulted in deth, ws life-thretening or required hospitlistion [7]. We lso included seizures requiring medicl ttendnce (ED nd/or hospitlistion) s mediclly importnt events. SAEs were reported to stte/territory helth deprtments nd the Therpeutic Goods Administrtion s required y legisltion. For this report, dt were compiled from 1 April through 31 August 2015 nd cumultive dt reported to helth uthorities weekly. After week 4 of surveillnce, progressive results were periodiclly mde puliclly ville online nd shred vi immunistion provider networks. For rpid signl detection, fst initil response cumultive summtion (FIR CUSUM) nd Byesin methods [8,9] were employed weekly to estimte the proility tht ny potentil sfety signl ws true or flse sed on predetermined expected nd threshold rtes of two ojective outcome mesures (fever nd medicl dvice/ttendnce sought) in reltion to the numer of reports received. Expected nd threshold rtes were set ccording to previous surveillnce results nd pulished studies. For fever, the expected rte ws 6% nd the threshold rte for triggering signl ws 13% [5,10-12]. Results Approximtely 75% of the 4,441 prents/crers invited greed to prticipte, resulting in 3,340 post-vccintion reports (Figure). The mjority of prent/crers responded within two hours of eing queried. Descriptive detils of prticipnts re presented in Tle 1. Weekly nlysis using FIR CUSUM nd Byesin methods (conducted 1 April through 5 July 2015) did not demonstrte sfety signl t ny time. After the third week of surveillnce (n = 877 cumultive reports), fever rtes remined less frequent thn 5% ech week nd medicl dvice/ttendnce rtes remined lower thn 2%. Prent/crer-reported fever ws recorded y 4.4% (n = 148); medicl dvice/ttendnce ws sought y 1.1% (n = 35). Detils on rections nd medicl dvice/ ttendnce sought re included in Tle 2. Of the 35 children who received medicl dvice/ttendnce, 23 reported fever. Five children experienced seizures, four of whom hd history of seizures (three: underlying neurologicl conditions; one: previous ferile seizures). The fifth seizure cse occurred in child dignosed with ferile virl illness. Only three of the children with seizures sought medicl ttendnce nd were thus clssified s hving SAEs; ll ttended n ED only. One dditionl SAE ws recorded in child hospitlised with n influenz-like illness nd fever. Two of the four children experiencing n SAE hd received Vxigrip, one hd received Flurix nd the other received Influvc. All reported improvement within dys. No significnt difference ws identified etween children who hd received one of the two most commonly used vccine rnds, Vxigrip or Flurix, nd who experienced fever or sought medicl dvice/ ttendnce. All other rnds hd een dministered in insufficient numers to relily report on differences (Tle 3). Children receiving other vccines concomitntly were significntly more likely to experience fever (60/687; 8.7%) thn those who did not (87/2,618; 3.3%) (p = 0.000). There ws no difference etween children with nd without n underlying condition regrding fever (29/400 (7.3%) vs 56/721 (7.8%)) or medicl dvice/ttendnce sought (9/400 (2.3%) vs 17/721 (2.4%)). Discussion Our novel system of ctive, prospective vccine sfety surveillnce, AusVxSfety, hs demonstrted in rel time tht 2015 southern hemisphere influenz vccines registered for use in young Austrlin children were sfe nd well-tolerted. Adverse event rtes reported y prents/crers remined low nd within expected rnges throughout the surveillnce period. The fever rte ws lower thn the pooled estimte (6.7%) in recent systemtic review of rndomised control trils of children ged six to 35 months receiving the first dose of trivlent influenz [12]. 2

3 Tle 1 Demogrphic detils of AusVxSfety prticipnts, Austrli, 1 April 31 August 2015 (n = 3,340) Vrile Response Numer Percentge Medin ge (rnge) 23.0 months ( ) Sex Mle 1,781/3, % Ethnicity Indigenous 119/2, % Underlying medicl condition c Yes 400/1, % Concomitnt vccine(s) received d Yes 687/3, % Sex unknown for 26 of 3,340 prticipnts. Ethnicity unknown for 821 of 3,340 prticipnts. c Underlying medicl condition not ville for 2,219 of 3,340 prticipnts (SmrtVx dt mngement system does not currently collect this vrile). d Dt on whether concomitnt vccine ws received unknown for 35 of 3,340 prticipnts. Tle 2 Adverse events reported y 2015 AusVxSfety prticipnts within three dys of vccintion, Austrli, 1 April 31 August 2015 (n = 3,340) Adverse event Numer Percentge Any dverse event 385/3, % Fever 148/3, % Seizure 5/3, % Injection site rection 67/3, % Vomiting/dominl pin 41/3, % Rsh 36/3, % Prticipnts who sought ny medicl dvice nd/or required ny medicl ttendnce 35/3, % Prticipnts ttending medicl fcility for consulttion with generl prctitioner or other medicl prctitioner 23/3, % Highest medicl dvice nd/or ttendnce reported Prticipnts telephoning medicl fcility or mediclly stffed helpline for dvice 4/3, % Prticipnts presenting to n emergency deprtment (not dmitted) 6/3, % Prticipnts hospitlised 2/3, % Of the five children with seizures reported, three presented to n emergency deprtment nd were thus clssified s hving serious dverse event. One child ws hospitlised with n unrelted condition not deemed serious dverse event. The other hospitlised child hd n influenzlike illness. Active, prospective vccine sfety surveillnce is superior to trditionl post-mrketing vccine sfety surveillnce which typiclly relies on pssive reporting. In Austrli, SMS technology hs lso een used to study vccine rections mong helthcre workers nd pregnnt women [13,14]. One study in the United Sttes lso used SMS follow-up of prents, detecting incresed fever rtes in children who hd concomitntly received trivlent influenz vccine nd 13-vlent pneumococcl vccine compred with those who received ech vccine lone [15]. Similrly, we reported n incresed (lthough low) rte of fever when influenz vccine ws dministered together with other vccines. This ws lso ssocited with significntly higher likelihood of seeking medicl dvice nd wrrnts further investigtion. Becuse lrge volumes of influenz vccine re distriuted nnully within short, defined periods, ctive surveillnce provides the opportunity to gin erly, relile ssessments of the sfety profiles of new vccines. As the numer of ville influenz vccines increses, otining timely sfety dt ecomes more importnt, prticulrly s strin composition my vry from seson to seson. In 2010 in Austrli, n unexpected increse in ferile rections following receipt of influenz vccintion in young children led to three month suspension of ll ntionl peditric influenz immunistion progrmmes [16]. Epidemiologicl nd lortory studies linked these rections to one mnufcturer s vccine (Fluvx or Afluri, iocsl) which is no longer registered for use in young children [16,17]; however, confidence in ll influenz vccines ws negtively impcted [18,19]. In response to these sfety concerns which hve resulted in low uptke of 3

4 Tle 3 Detils of influenz vccines dministered to AusVxSfety prticipnts, Austrli, 1 April 31 August 2015 (n = 3,340) Brnd (mnufcturer) Vxigrip (Snofi-Psteur) Flurix (GlxoSmithKline) Influvc (BGP Products) Agrippl (Novrtis Vccines nd Dignostics) FluQudri (Snofi Psteur) Vccine type Numer of vccines dministered (n = 3,336) Numer of prticipnts with fever y rnd Numer of prticipnts who sought medicl dvice/ttendnce y rnd n % n/n % n/n % Trivlent 3, /3,075 c 4.3% 28/3,075 d 0.9% Trivlent / / Trivlent /47 NR 2/47 NR Trivlent /11 NR 0/11 NR Qudrivlent /14 NR 1/14 NR NR: not relevnt. Brnd unknown for four prticipnts. All dministered vccines except for FluQudri were trivlent. Qudrivlent vccines (FluQudri/ FluQudri Junior nd Flurix Tetr (GlxoSmithKline)) were ville for use for the first time in Austrli in 2015 ut were not funded under the Ntionl Immunistion Progrm. c p = for rtes of fever mong those who received Vxigrip (4.3%) compred with those who received Flurix (4.8%) clculted using Person s chi-squre test. d p = for rtes of medicl dvice/ttendnce sought mong those who received Vxigrip (0.9%) compred with those who received Flurix (2.1%) clculted using Fisher s exct test. sesonl influenz vccines in children, AusVxSfety surveillnce dt hve een le to provide ressuring results. Dt otined from prentl reporting should e interpreted with cre. Consequently, AusVxSfety reports on outcomes which re the most ojective: fever nd medicl dvice/ttendnce sought within three dys of vccintion. Although these provide less precision thn results otined in more forml follow-up such s clinicl trils, this is unlikely to reduce our system s sensitivity for detecting SAEs, of which medicl dvice/ ttendnce sought cn e considered good proxy. This ws demonstrted in the epidemiologicl investigtion of the 2010 increse in ferile rections [16]. An dvntge of our system is its potentil dptility for monitoring new vccines, such s live ttenuted influenz vccine, lthough this is not yet ville in the southern hemisphere. Another dvntge is its ility to provide rpid rel-time feedck to inform progrmme rollout nd vccine promotion. In ddition, AusVxSfety s flexiility my e vlule in situtions where vccine sfety dt re limited, such s for pndemic vccines. The timeliness of our results lso mkes them vlule eyond Austrli; our dt my e of interest to counterprts in the northern hemisphere prepring for 2015/16 vccintion using vccines comprised of the strins dministered in the 2015 southern hemisphere seson. Our system, which is le to report dverse events within dys of vccintion, is s ner to rel time s possile. Such timeliness is fesile thnks to the strong collortion with prents/crers nd providers nd the use of SMS technology for reporting rections. We nticipte eing le improve our system y including more prticipnts in future yers. To our knowledge, AusVxSfety is the only ctive influenz vccine sfety surveillnce system for young children nlysing nd reporting dt on weekly sis, llowing sfety deliertions on vccines within mere weeks of influenz vccintion commencing. Our ility to provide erly nd relile sfety profiles of sesonl influenz vccines for children is likely to improve pulic confidence nd vccine uptke, which we will continue to ssess. AusVxSfety 2015 surveillnce tem Kren Orr, Gulm Khndker, Kevin Yin, Dvid Durrheim, Crig Dlton, Slly Munnoch, Michelle Butler, Jody Stephenson, Stephen Clrke, Keir Glsgow, Luren Dlton, Brendn McMulln, Gerldine Dunne, Jim Buttery, Gowri Selvrj, Annette Alfci, Peter Eizenerg, Pul Effler, Peter Richmond, Peter Jcoy, Prveen Fthim, Luren Trcey, Griel Willis, Jennifer Kent, In Peters, Rchel West, Kri Jrvinen, Susn Vlck, Deorh Judd, Melind Hssll, Juli Clrk, Stephen Lmert, Michel Gold, Griell Lincoln, Roslind Wey, Kylene Prince. Acknowledgements AusVxSfety surveillnce ws funded under contrct with the Austrlin Government Deprtment of Helth. We would like to thnk the AusVxSfety Steering Committee memers for their contriution to oversight of the 2015 surveillnce effort. We would lso like to express our grtitude to the stff 4

5 t our prticipting hospitls, clinics nd generl prctices, s well s the prents/crers of children who prticipted in nd supported 2015 AusVxSfety surveillnce. Conflict of interest None declred. Authors contriutions AP served s AusVxSfety surveillnce coordintor for 2015, drfted the mnuscript, nd conducted dt nlysis nd interprettion of results. PC contriuted to the design nd implementtion of the AusVxSfety surveillnce system, served s coordintor/recruiter of the Hunter New Englnd re surveillnce sites, reviewed nd contriuted to the mnuscript drft. AL contriuted to the design nd implementtion of the AusVxSfety surveillnce system, recruited generl prctice site prticipnts, reviewed nd contriuted to the mnuscript drft. AR contriuted to the design nd implementtion of the AusVxSfety surveillnce system, served s coordintor of the Western Austrli surveillnce sites, conducted dt collection nd nlysis, nd reviewed nd contriuted to the mnuscript drft. DW served s coordintor of the Western Austrli surveillnce sites, conducted dt collection nd nlysis, nd reviewed nd contriuted to the mnuscript drft. TS contriuted to the design nd implementtion of the AusVxSfety surveillnce system, conducted dt nlysis, nd reviewed the mnuscript drft. CB contriuted to the design nd implementtion of the AusVxSfety surveillnce system nd reviewed nd contriuted to the drft mnuscript. NC contriuted to the design nd implementtion of the AusVxSfety surveillnce system nd reviewed nd contriuted to the drft mnuscript. KM contriuted to the design, implementtion nd coordintion of the AusVxSfety surveillnce system, nd drfted the mnuscript. References 1. AusVxSfety. AusVxSfety Finl report to the Austrlin Government Deprtment of Helth for Contrct HEALTH/082/2014. Sydney: Ntionl Centre for Immunistion Reserch nd Surveillnce of Vccine Preventle Diseses; Dec Khndker G. Going ntionl: AusVxSfety 2014 nd eyond. Active surveillnce for dverse events following immunistion - new methods in vccine phrmcovigilnce. Conference on Vccine sfety: ctive surveillnce for dverse events following immunistion new methods in vccine phrmcovigilnce; 29 Oct 2014; North Sydney, Austrli. 3. Hull B, Dey A, Berd F, Menzies R, Brotherton J, McIntyre P. Annul immunistion coverge report Westmed: Ntionl Centre for Immunistion Reserch nd Surveillnce of Vccine Preventle Diseses; Aville from: ncirs.edu.u/ssets/surveillnce/coverge/2013-covergereport-finl.pdf 4. Austrlin demogrphic sttistics, Mr Sydney: Austrlin Bureu of Sttistics. [Accessed: 30 Septemer 2015]. Aville from: nsf/mf/ CshmnP, MoerleyS, DltonC, StephensonJ, ElvidgeE, ButlerM, et l. Vxtrcker: Active on-line surveillnce for dverse events following inctivted influenz vccine in children. Vccine. 2014;32(42): DOI: /j. vccine PMID: LeeA, RegnAK, PetersIJ, LeeC, LeeG, EfflerPV. 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