PRIME: Immunogenicity Randomized Controlled Trial Risk of Bias Tool

Transcription

1 PRIME: Immunogeniity Rnomize Controlle Tril Risk of Bis Tool Question 1 Is the stuy rnomize? 2 Blining of prtiipnts n personnel Blining of outome ssessment (e.g., speimens were teste without knowlege of pre/post PCV sttus or stuy rm) Inomplete outome t (e.g., the perent of those rnomize to those nlyze) Ws inustry (i.e., GSK or Pfizer) involve in this stuy? Answers. Yes. Control group ut not rnomize. No ontrol rm/group. Unler e. Not stte/full text not ville (ie. Poster or strt) f. Not pplile. Doule-lin. Single-lin (either prtiipnts or stuy personnel). Open lel. Unler e. Not stte/full text not ville (ie. Poster or strt). Yes. No (.e., not line or no ontrol rm for the relevnt outome of interest). Unler. Not stte/full text not ville (ie. Poster or strt). 90% or more of those rnomize were inlue in the nlysis of the relevnt outome of interest. Fewer thn 90% were nlyze. Unler. Not stte/full text not ville (ie. Poster or strt). No. Yes, fune ll or in prt y Inustry ut onute entirely y inepenent investigtors (e.g., no o-uthors from inustry; l work not performe y Inustry). Yes, onute ll or in prt y inustry (e.g., nlyses or l work performe y Inustry). Unler e. Not stte/full text not ville (ie. Poster or strt) 6 Other Risk of Bis Plese omment on other ftors tht my introue is

2 Immunogeniity Rnomize Controlle Tril Risk of Bis Assessments RefID Referene (Author,Yer) Q1rn_ns Q1rn_omments Q2linpr Q2linprt_omments t_ns 1412 Esposito, 2010 "Sujets were rnomly ssigne in 1:1 rtio to one of the two vine groups" "This ws phse 3... oule-lin, multienter tril Tretment llotion ws onele from ll sujets, stuy stff, n those ssessing the outomes." 444 Llwni, 2014 "This ws phse III rnomize stuy" Stuy only ssesse 1 vine prout, n "The stuy ws onute in n open mnner, s the prtiipnts from the ifferent groups reeive the stuy vine oring to ifferent vintion sheules." 263 Lim, 2014 "Infnts were su-rnomize (1:1) to two susets" "The primry vintion phse ws oule-line", while the phse tht ssesse the impt of ooster ose ws "onute in n open-lel mnner". Q3linout Q3linout_omments _ns "Tretment llotion ws onele from ll sujets, stuy stff, n those ssessing the outomes." No mention of stuy personnel eing mske. Q4inomp_ Q4inomp_omments ns Of the 606 rnomize hilren (n=303 in eh of the 2 rms), "285 (94.1% sujets in the group n 281 (92.7% in the PCV7 group omplete the entire stuy". However, s seen in Tles 4 n 5, the % of infnts ssesse vrie y vine serotype n often ws <90% of rnomize hilren. Aoring to Figure 2, etween 74.7% % of enrolle hilren were nlyze. Q5Inustry Q5inustry_omments Q6othis_omments Overll_Assessment Overll_Assessment _Ans : PICO1/PICO2 : PICO 3, Stuy ws fune y grnt from Wyeth n severl of the uthor ffilitions liste re for Wyeth., Stuy ws onute n fune y GSK. Not stte Aoring to Figure 1, only roun ~50% of enrolle hilren omplete the ooster phse for nlysis." Booster oul only e one in Singpore setting., Stuy ws onute n fune y GSK hilren enrolle per rm so not ig stuy UNCLEAR: not sure if l nlysis ws line, vrie ompleteness of outome t UNCLEAR: 88 Vn Westen, 2015 Infnts orn in the Netherlns uring Septemer-Deemer 2011 were enrolle in ontrolle prllel group intervention stuy ompring immuno efore n fter ooster ose with PCV10 or. Chilren were rnomly ssigne to groups in whih n intrvenous loo smple ws ollete efore n fter the ooster ose t ifferent times. 108 Hmlu, 2015 Stuy stff llote prtiipnts with prtiipnt numer n rnomly ssigne (4:4:5 rtio) them to reeive PCV10 t either 6 n 14 weeks with 9 month ooster (2+1 group); ge 6, 10, n 14 weeks (3+0 group), or no vine until ge 10 n 11 months. 116 Gzinowski, 2015 Helth infnts were rnomize 1:1 to reeive +P80 or without P80 given t ges 2,3,4 n 12 months with onomitnt vines 151 Mrtinón, 2015 Phse IV, open-lel 2-rm, multienter, prllel-group stuy with 2 groups: pre-term n term infnts 600 Spijkermn, 2013 "400 infnts were rnomly ssigne (1:1:1:1) to reeive Rnomiztion ws performe y rnom numer genertor 13 using lok rnomiztion with rnomly vrying lok size" 761 Kim, 2013 "Sujets were rnomly ssigne in 1:1 rtio to reeive either or PCV7 se on rnom ssignment sheule prepre y the sponsor." stff memers n prents were wre of the intervention L stff were line Aoring to Figure 1, roughly were rnomize n inlue in the nlysis Open lel stuy Lortory stff were mske to intervention group ssignment Doule-lin multienter tril Lortory personnel remine line t ll times Aoring to Figure 1, greter thn 90% of hilren enrolle h loo rws t 10 months Aoring to Supplementl Digitl Content 2, roughly 93% of prtiipnts were in the evlule immunogeniity popultion Open lel stuy Not stte, Aoring to Fig. 1, roughly 98% were inlue in the infnt series nlysis n roughly 88% were inlue in the toler ose nlysis Sine this stuy ssesse ifferent vine sheules, y nture, it ws open lel "This ws prllel-group, rnomize, oule-lin tril " "Stuy stff memers n prents were wre of the hil s llote immuniztion sheule, ut lortory stff ws not" Aoring to Figure 1, 90.5% of rnomize hilren were inlue for nlysis in the Per Protool nlysis (92% for ITT nlysis). Not stte Aoring to Figure 1, 91.1% of rnomize hilren were inlue for nlysis. Stuy ws fune y the Duth Ministry of Helth; however one uthor hs reeive unrestrite reserh support from Pfizer, grnt support for vine stuies from Pfizer n GSK, n fes pi to her institution for visory ors or prtiipnts in inepenent t monitoring ommittees for oth ompnies. GSK fune the stuy through n investigtor originte grnt, ut h no role in the esign or mngement of the stuy, t nlysis n interprettion, or the finl eision to sumit to pulition Stuy ws sponsore y Wyeth, whih ws quire y Pfizer; ssys were preforme in linil tril ssy testing lortories owne y Pfizer IgG n OPA testing ws performe y Pfizer's Vine Reserh linil testing lortory Some uthor reporte hving reeive grnts & fees from inustry. Pfizer provie 1400 vines for the stuy. Stuy ws prtilly onute n fune y Pfizer. Smll smple size UNCLEAR UNCLEAR 828 Wekx, 2012 "Sujets were rnomly ssigne in 1:1 rtio" "This phse 3, rnomize, tive-ontrolle, oulelin, prllel-group, multienter tril..." Not stte Aoring to Figure 1, 85.8% of the n=354 rnomize hilren were inlue for nlysis. Some uthors re ffilite with Wyeth, Wyeth sponsore the stuy, n ontriute to the stuy's esign, t olletion, nlysis, et.

3 1034 Mrtinón-Torres, 2012 "Sujets were rnomly llote in 1:1: rtio" 4477 Outol, week ol infnts were 1:1:1:1:1:1 - rnomize 4475 Mulholln, 2016 e Not stte/full text not ville (ie. Poster or strt) "This ws oule-lin stuy, n ll prtiipnts n stuypersonnel were lin to tretment llotion." Not stte Aoring to the text, 74.8 % of the n=449 rnomize hilren were inlue for nlysis fer the toler ose. Some uthors re ffilite with Wyeth, Wyeth sponsore the stuy, n ontriute to the stuy's esign, t olletion, nlysis, et. oserver-lin stuy Not stte (poster) Not stte (poster) Fune y GSK; some outhors GSK ffilite e Not stte (presenttion from SAGE WG) Not stte (presenttion from SAGE WG) Not stte (presenttion from SAGE WG) e Not stte (presenttion from SAGE WG) 4468 Moisi, unpulishe Infnts n tolers rnomize using rnom numer genertor funtion se on uniform proility istriution; performe in loks of 20, fter strtifition y lini for infnt group Open lel stuy No uthor ffilitions liste, so not ertin tht outhors were not inustryffilite 4323 Flup-Peurrui, 2016 infnts were rnomize 3:3:3:1:1:1 Open lel stuy ll stuy stff were wre of tretment llotion 3933 Verhgen, 2016 pre-vine time point the omprtor for post-vine GMT 1052 Hung, 2011 "Sujets were rnomly ssigne in 1:1 rtio" 1088 Knuf, 2012 " Infnts were susequently rnomize (1:1) to PHiD-CV or 7vCRM stuy group" e Not pplile sine only 1 intervention "This rnomize, oulelin, multienter tril" The phse of the stuy whih involve reeipt of either PCV7 or PCV10 ws single lin Not stte Not stte Fune prtilly y Pfizer Venezuel, ut no outhors ffilite with inustry Not stte Aoring to Figure 1, 97.0% of the 168 rnomize hilren were inlue for nlysis. "Serum liquots were store t - 20 C until line nlysis t GSK Biologils lortory in Rixensrt, Belgium." Aoring to Figure 1, 79.1% of the 134 rnomize hilren were inlue for nlysis. One o-uthor hs Pfizer ffilition, stuy ws sponsore y Wyeth, n Wyeth ontriute to the stuy's onut. One o-uthor hs GSK ffilition, stuy ws prtilly sponsore y GSK, n GSK ws involve in ll stges of onut n nlysis. UNCLEAR: GSK stuy, lining of l personnel n ompleteness of outome t not stte UNCLEAR: Not enough informtion to evlute High uren of IPD in SA HIGH: no ontrol inigenous popultion, group exept for nturl history of pneumo pre-vine time isese & oloniztion point ffeting hnge in ntioy response over time Smll smple size 1101 Grimprel, 2011 "Eligile sujets were rnomly llote in 2:1:1 rtio... using per-mute lok rnomiztion sheule" 1008 Llwni, 2012 "Helthy infnts werernomize (2:1 tretment llotion rtio) " 1105 Kim, 2011 "Infnts were rnomize (3:1 tretment llotion rtio)" "All prtiipnts, stuy stff, n those ssessing the outomes were line to the group ssignment." "The stuy ws onute in single-line mnner mening tht the investigtor ws wre of the tretment ssignment ut the infnt s prents/gurins were not" "single-lin, rnomize, ontrolle tril" "All prtiipnts, stuy stff, n those ssessing the outomes were line to the group ssignment." "A potentil limittion of this stuy ws the sene of investi-gtor lining" Aoring to Figure 1, 80.7% of the 613 rnomize hilren were inlue for nlysis. Aoring to Figure 1, 95.8% of the 360 rnomize hilren were inlue for nlysis. Not stte Aoring to Figure 1, 83.3% of the 503 rnomize hilren were inlue for nlysis Vesikri, 2011 f Infnts were ssigne vine sheule se on ge, n only 1 vine prout ws use. The referene group ws hilren who h reeive the vine through the norml hilhoo vine sheule. open lel Not stte Aoring to Figure 1, 88% of the 600 rnomize hilren were inlue for nlysis. 548 Ousny, 2013 " A rnomistion loking sheme (2:1 rtio)... ws use to ensure tht lne etween tretments ws mintine" 1142 Ruiz-Plios, 2011 No ontrol group present- "The ojetives of this phse III, single-rm, open-lele stuy..." 443 Juergens, 2014 "In rief, eligile sujets were rnomly ssigne t 1:1 rtio to reeive or PCV7." 452 Ousny, 2014 This is follow-up to n erlier stuy tht rnomize hilren to PCV10 primry series vintion or to ontrol group. Previously vinte n ontrol group hilren were then invite to prtiipte in this ooster phse stuy. "In this open, rnomise, ontrolle stuy". "The ojetives of this phse III, single-rm, openlele stuy..." "This rnomize oulelin tril ws onute in Isrel..." Sine this stuy ssesse ifferent vine sheules, y nture, it ws open lel Not stte Aoring to the Tril Profile figure, 90% of the 120 rnomize hilren were inlue for nlysis. Not stte Aoring to Figure 1, 95.2% of the 230 rnomize hilren were inlue for nlysis. Not stte Authors present n=354 totl hilren rnomize, ut then fous on the n=200 hilren suset (100 PCV7, 100 ) selete for this nlysis. Unler. Not stte Aoring to Figure 1, 86.5% of the 119 rnomize hilren were inlue for nlysis. Some uthors re ffilite with Wyeth, Wyeth sponsore the stuy. Some uthors re ffilite with GSK, n GSK sponsore the stuy n ws involve in ll stges of onut n nlysis. Some uthors re ffilite with GSK, n GSK sponsore the stuy n ws involve in ll stges of onut n nlysis. Some uthors re ffilite with GSK, n GSK sponsore the stuy n ws involve in ll stges of onut n nlysis. Some uthors re ffilite Smll smple size with GSK, n GSK sponsore the stuy n ws involve in ll stges of onut n nlysis. Some uthors re ffilite Comprison to Europen with GSK, n GSK ohort sponsore the stuy n ws involve in ll stges of onut n nlysis. Some uthors re ffilite with Pfizer & Wyeth sponsore the stuy. UNCLEAR: not stte if l personnel line, somewht lower ompleteness of t HIGH: Mexin group ompre to Europen group Some uthors re ffilite with GSK, n GSK sponsore the stuy n ws involve in ll stges of onut n nlysis. Smll smple size

4 538 Togshi, 2013 "This ws n open-lel stuy tht h only 1 tretment rm" This ws n open-lel stuy tht h only 1 tretment rm 558 Diez-Domingo, 2013 "Sujets were rnomize in 1:1 rtio" "Phse 3, prllel-group, rnomize, tiveontrolle, oule-lin, multienter tril" 593 Dgn, 2013 "Helthy infnts were rnomize (1:1) to reeive PCV7 or " 602 Grnt, 2013 f Stuy h n oservtionl esign, where loo smples were tken from hilren who h lrey reeive PCV s prt of their routine vine sheule 647 Pyton, 2013 "Sujets were rnomly ssigne in 2:2:2:1 rtio to reeive 1 of 3 lots of or PCV7 using we se rnomiztion system." 757 Singleton, 2013 f Stuy h n oservtionl esign- "hilren were offere s pproprite for ge n prior PCV7 history"". No rnomiztion ourre. "This rnomize oulelin tril..." "This ws phse 3, rnomize, oule-lin, multienter stuy" Not stte Aoring to Figure 1, 95.3% of the 193 rnomize hilren were inlue for nlysis. Not stte Aoring to Figure 1, 94.0% of the 619 rnomize hilren were inlue for nlysis. Not stte Aoring to Figure 1, 93.9% of the 1,866 rnomize hilren were inlue for nlysis. Not pplile: Stuy h n oservtionl esign, where loo smples were tken from hilren who h lrey reeive PCV s prt of their routine vine sheule. Stuy personnel therefore i not minster vines to prtiipnts Not stte Supplementry figure 1 provies informtion on how mny ser were ollete t the eginning verus ser ultimtely nlyze. Aoring to Suppl Figure 1, 72.5% of the 561 ser ollete were inlue for nlysis. Suppl Figure 1 ville here: /rtile?i= /journl.pon e #s5 Not stte Aoring to Figure 1, 72.6% of the 1,712 rnomize hilren were inlue for nlysis. "This ws phse 3, openlel tril" 800 Diko, 2013 Stuy h no ontrol group "This phse III, openlel, single-enter stuy" 815 Brito, 2013 "This phse 3, open-lel, single-rm, multienter tril" 838 Amekr, 2013 "This ws phse 3, rnomize, tiveontrolle, oule-lin tril" 922 Lin, 2012 "This ws single-rm, open stuy" "This ws single-rm, open stuy" 3824 Zhu, 2016 phse 3, rnomize tril; infnts rnomize 2:2:2:1 to PCV7 or n ifferent sheules 3832 Truk, 2016 rnomize, ontrolle tril open lel for prtiipnts n linil tril stff Not stte Aoring to the text, 48.8% of the 373 enrolle hilren (no rnomiztion ourre) omplete the full vintion series per protool. Even fewer h loo rwn within the protool-speifie time perio Only 1 intervention group Aoring to the text, 95.2% of the 147 enrolle hilren omplete the stuy. "This phse 3, open-lel, Only 1 intervention group Aoring to Figure 1, 81.3% of single-rm, multienter tril" the 225 enrolle hilren omplete the toler ose. "This ws phse 3, rnomize, tiveontrolle, oule-lin tril" Not stte Aoring to Figure 1, 54.8% of the 709 enrolle hilren were inlue for nlysis fter the toler ose. Single rm stuy Aoring to Figure 2, 95.2% of the 230 enrolle hilren were inlue in the oring-toprotool immunogeniity ohort. n vines were ministere not speifie in text n 92% of rnomize sujets nlyze for infnt series; 82% fter toler ose line for lortory stff 79%-85% of inlue sujets ville t follow up time points 3878 Mrtinon-Torres, 2015 no ontrol group, just preterm infnts n full term infnts who oth reeive open-lel ssys one in Pfizer l 88% prt of evlule immunogeniity popultion 3916 Truk, 2016 rnomize to either or PCV10 ooster open lel for prtiipnts line for lortory stff 87% ville for memory B ell n linil tril stff n ntioy nlysis 3924 Mrtinon-Torres, 2017 no ontrol group, just preterm infnts n full term infnts who oth reeive open-lel ssys one in Pfizer l 80% follow up t 1 yer, 71% t 2 yers 3675 Pomt, 2016 infnts rnomize to either PCV10 or e not stte in text not stte in text 81% of infnts ville for postprimry rms, no ontrol group nlysis 3696 Blloh, 2016 infnts rnomize to reeive one of two e sheules, no ontrol group not stte ut unlikely s ifferent ges for reeipt of oses n loo rw not stte totl N enrolle not stte, ut stuy rm 2m/4m h 235 infnts n 2m/6m only h 149 n not expline why Some uthors re ffilite with Pfizer, n Wyeth sponsore the stuy. Some uthors re ffilite with Pfizer, n Wyeth sponsore the stuy. Some uthors re ffilite with Pfizer, n Wyeth sponsore the stuy. Stuy ws prtilly fune y Pfizer ut onute y uthors with no inustry ffilitions. Some uthors re ffilite with Pfizer, n Wyeth sponsore the stuy. Some uthors re ffilite with Pfizer, n Wyeth sponsore the stuy. Some uthors re ffilite with GSK n GSK sponsore the stuy. Some uthors re ffilite with Pfizer, n Wyeth sponsore the stuy. Some uthors re ffilite with Pfizer, n Wyeth sponsore the stuy. Some uthors re ffilite with GSK n GSK sponsore the stuy. fune y Pfizer, some outhors from Pfizer GSK support ut i not hve role in stuy esign n nlysis Pfizer outhors involve in stuy GSK support ut i not hve role in stuy esign n nlysis Pfizer outhors involve in stuy Very smll smple size Clinil hol on PCV trils in Ini euse of some verse events UNCLEAR: 1 rm, so fol-rise ompre pre n post vintion. No efinition of GMFR omprison. No mention of uren of Spn in ommunity so potentil for nturl oosting. UNCLEAR: hnging epiemiology of irulting STs my lso impt immunogenity y nturl exposure HIGH: smll smple size, missing outome t UNCLEAR: inomplete outome ssessment : one stuy rm not line proly euse ifferene in sheule : slightly lower outome follow up % :: Pfizer l onute ssys : Pfizer l onute ssys n lower follow: up t 2 yers post no mention of inustry in poster vine onte y GSK : though ifferent n of rms, the finings re onsistent with wht we woul expet n so likely relile results 3721 Silfverl, 2009 infnts rnomize to reeive one of two sheules, no ontrol group open lel not stte in text 89% of sujets inlue in nlysis 3722 Vesikri, 2009 primry sheule: infnts rnomize, e not stte line nlyses onute t GSK ooster sheule: prtilly rnomize se ls on wht vines reeive s primry 90% for primry phse n 95% for ooster phse fune y GSK n one of the o-uthors employe t GSK, ssys one t GSK l fune y GSK, ssys one in GSK ls n GSK involve in stuy esign & onut

5 3723 Wysoki, 2009 rnomize ut no ontrol open lel line nlyses onute t GSK ls 1090 Vnerkooi, 2012 "Sujets were rnomize 1:1" "This ws phse III, prllel-group, oulelin, multi-enter tril" 1126 Diko, 2011 "The ojetives of this phse III, rnomize, open, ontrolle stuy" 798, 3724, 3725 Ruiz-Plios, 2013 tolers rnomize to 1 of 3 osing sheules "The ojetives of this phse III, rnomize, open, ontrolle stuy" 3754 vn en Bergh, 2016 rnomize to PCV10 or PCV7 rms stff memers wre of stuy rm llotion ut prents were not open lel "Lortory personnel responsile for immunogeniity testing were line to the tretment group." ssessment for immunogeniity seonry outome (fter sfety) n prespeifie s only n=180 per group Not stte Aoring to Figure 1, 94.3% of the 603 rnomize hilren omplete the toler series for nlysis. Not stte Aoring to Figure 1, 91.9% of the 358 rnomize hilren were inlue for in the ATP immunogeniity ohort. 93% of sujets omplete protool for immunogeniity nlysis lortory tehniins not wre of stuy rm llotions 93% of sujets omplete protool for immunogeniity nlysis Some uthors re ffilite with Pfizer, n Wyeth sponsore the stuy. Some uthors re ffilite with GSK n GSK sponsore the stuy. GSK fune stuy n involve in esign, outhors employe t GSK, GSK ls GSK fune stuy n involve in esign, outhors employe t GSK, GSK ls Stuy of sfety n immunogeniity with ifferent oministere vines : GSK stuy, primry ojetive sfety 2226 Tregnghi, 2014 RCT Doule-lin multienter tril 2367, 3718 Berml, 2011 infnts rnomize to reeive either PCV10 or PCV7 "personnel involve in t gthering, proessing, n nlysis n sfety ssessment were lin to vine llotion" oule-lin "ser were nlyze in line mnner" 67% for PP nlysis of primry series, 45% for PP nlysis of ooster 93% of sujets omplete protool for immunogeniity nlysis 3363 Vesikri, 2016 rnomize, ontrolle luster tril oule-lin not stte 82% of infnt group ville for nlysis; 74% of th up group inlue in nlysis GSK fune stuy n out 264 infnts exlue : GSK stuy, involve in esign, outhors from immunogeniity rms still lrge numers employe t GSK, GSK ls euse of inorret onsent in immunogeniity form. High rte of ttrition nlysis etween primry n ooster time points. GSK fune stuy n ooster phse ontinue involve in esign, outhors from primry phse of employe t GSK, GSK ls omprison RCT etween PCV10 n PCV7 GSK fune stuy n involve in esign, outhors employe t GSK, GSK ls UNCLEAR: not sure if l nlysis ws line v v v 1424 Brynt, 2010 Infnts (n 249) were rnomly s- signe to reeive (n 122) or PCV7 (n 127) e not stte not stte in text 91.6% of the infnts (228 of 249) omplete the primry vintion series Timo, 2010 A totl of 1650 sujets (1235 in the three PHiD-CV groups n 415 in the 7vCRM group) were enrolle for the primry vintion phse n 1112 sujets for the ooster phse (737 in the PHiD-CV prime n ooster group, 92 in the 7vCRM prime n ooster group n 283 in the 7vCRM prime n PHiD-CV ooster group). e not stte Blin nlyses were onute t GSK lortories, Rixensrt, Belgium. A 1546 Lhni 2015 only 1 intervention n historil ontrol This ws n open, nonrnomize stuy onute y the sme investigtors in 2 of the sme geogrphil res (Glouestershire/Hertforsh ire) in tht ssesse ntioy responses in infnts 1 month fter primry immuniztion with the sme vines n sheule n with smples teste y the sme lortories n ssys s in this evlution Dr Brynt hs een n investigtor on linil trils fune y Wyeth Phrmeutils, GlxoSmithKline, Novrtis, MeImmune, Astells, n Johnson n Johnson n hs serve s onsultnt to Wyeth n Astells, reeive honorri from Snofi Psteur n Aott for letures n from GlxoSmithKline for servie on n visory or; Dr Blok hs een n investigtor on linil trils fune y Wyeth, hs serve s n visor to Wyeth, hs serve s linil investigtor on trils fune y GlxoSmithKline n Merk, n hs serve on n visory or for Merk; Dr Bker ws n employee of Wyeth t the time the stuy ws onute; n Drs not stte e not stte UNCLEAR: lot of missing info not stte in text 95% ompleteness This report is inepenent Historil ontrol , reserh ommissione n stuy fune y the Deprtment of Helth Poliy Reserh Progrmme (N- tionl Vine Evlution Consortium, 039/0031). The Immuniztion, Hep- titis n Bloo Sfety Deprtment hs provie vine mnuftures with post-mrketing surveillne reports (not pertussisontining vines to te), whih the ompnies re require to sumit to the UK Liensing Au- thority in ompline with their Risk Mngement Strtegy. A ost reovery hrge is me for these reports. : historil ontrols lso from er

6 1573 Iwt, 2015 This phse III, rnomize, open-lel, multienter stuy (NCT ) onute in Jpn ssesse the immunogeniity, sfety, n retogeniity of 10-vlent pneumool nontypele Hemophilus influenze protein D onjugte vine (PHiD- CV, given intrmusulrly) o-ministere with iphtheri-tetnus-ellulr pertussis vine (DTP, given suutneously). This phse III, rnomize, open-lel, multienter stuy (NCT ) onute in Jpn ssesse the immunogeniity, sfety, n retogeniity of 10-vlent pneumool nontypele Hemophilus influenze protein D onjugte vine (PHiD-CV, given intrmusulrly) oministere with iphtheri-tetnus-ellulr pertussis vine (DTP, given suutneously) no, lso not stte in the rtile oring to figure 1, originlly there were 360 iniviuls who oul e rnomize n fter the whole series there were 216 in the PHID-CV group n 115 in the onrol group fter ooster phse so.919 or 92% GlxoSmithKline Biologils SA ws the funing soure n ws involve in ll stges of the stuy onut n nlysis. Glx- osmithkline Biologils SA lso took responsiility for ll osts ssoite with the evelopment n pulishing of the present mnusript vn en Bergh, helth uth hilren were rnomly ssigne in this single lin stuy strt, not stte >70% enrolle sujets evlute for ooster ose GlxoSmithKline Biologils provie the funing 1957 Prymul, 2014 helth infnts were rnomize (1:1:1:1) prtilly line stuy strt, not stte strt, not stte GlxoSmithKline Biologils provie the funing 2089 Horn, 2014 rnomize (1:1) oule lin strt, not stte strt, not stte GlxoSmithKline Biologils provie the funing 2167 Wn, infnts rnomize in n open rnomize ontrolle tril 1181 vn en Bergh, 2011 "In single-lin, single-enter, rnomize "In single-lin, singleenter, ontrolle tril in the Netherlns" rnomize ontrolle tril in the Netherlns" 1229 Lgos, 2011 "hilren rnomize to reeive three oses of phid-v (phid-v group) or heptitis vine" 1262 Gzinowski, 2011 "helthy infnts were rnomly ssigne in 1:1 rtio" to reeive 1 of 2 lots of 1335 Snpe, 2010 "This phse III, rnomize, oule-lin, tive-ontrolle stuy" 1379 Yeh, 2010 "This phse 3, rnomize, oule-lin, tive-ontrolle, multi enter tril" 1406 Kieninger, 2010 "This ws prllel-group, rnomize, tive-ontrolle, oule-lin, multienter tril" 1407 Vesikri, 2010 "In this open, ontrolle stuy, 325 helthy hilren ge 12to 14 months were rnomize to 1 of 3 groups" 2202 Wijmeng, 2015 e. Not stte/full text not ville (ie. Poster or strt) A single-entre, prllel-group intervention stuy with two groups (PCV10 reipients n reipients) ws onute in the Netherlns mong infnts eligile for the routine Ntionl Immuniztion Progrm (NIP): vintions t 2, 3, 4 n 11 months of ge, or the 3 +1 (primry plus ooster) sheule "There were 2 stuy stges: n oserver-lin, rnomize, ontrolle primry vintion stge (106208/NCT ) n n oserver-lin ooster/th-up vintion stge" strt, not stte strt, not stte no onflits of interest Not stte Aoring to Figure 1, 72.6% of the 797 rnomize hilren were inlue in the ATP ohort for immunogeniity. Not stte Aoring to Figure 1, 65.4% of the 240 enrolle hilren were inlue in the ATP immunogeniity ohort. "This ws phse 3, prllelgroup, Not stte Aoring to Figure 1, 96.3% of rnomize, oule- lin, multi enter (9 enters in Poln) tril" the 269 rnomize hilren were inlue in the finl nlysis. "All stuy sites, prtiipnts n relevnt sponsor stff remine line to the vines reeive uring the stuy." "This phse 3, rnomize, oule-lin, tiveontrolle, multi entertril" "This ws prllel-group, rnomize, tiveontrolle, oule-lin, multienter tril" "In this open, ontrolle stuy, 325 helthy hilren ge 12to 14 months were rnomize to 1 of 3 groups" This ws n open-lel stuy for prents n stuy stff, ut immunogeniity nlysis ws performe line. " lortory stff remine line to the stuy groups t oth these stges." "Prtiipnts, stuy stff, n those who ssesse outomes were line to the group ssignment" "All prtiipnts, stuy stff, n those ssessing theoutomes were line to the group ssignment" "Potentil limittions of this stuy inlue the reltively smll smple size n the lk of investigtor lining" This ws n open-lel stuy for prents n stuy stff, ut immunogeniity nlysis ws performe line. Aoring to Figure 1, 68.8% of the 286 rnomize hilren were inlue in the toler perprotool nlysis fter ompleting the toler stge. Aoring to Figure 1, 69.3% of the 666 rnomize hilren were inlue in the toler evlule immunogeniity popultion. Aoring to Figure 1, 90.4% of the 605 rnomize hilren were inlue in the toler evlule immunogeniity popultion. Aoring to Figure 1, 96.3% of the 325 rnomize hilren were inlue in the ATP immunogeniity ohort. unler, i not stte this numer Some uthors re ffilite with GSK n GSK sponsore the stuy. Some uthors re ffilite with GSK n GSK sponsore the stuy. Some uthors re ffilite with Pfizer, n Wyeth sponsore the stuy. Some uthors re ffilite with Pfizer, n Wyeth sponsore the stuy. Some uthors re ffilite with Pfizer, n Wyeth sponsore the stuy. Some uthors re ffilite with Pfizer, n Pfizer onute the pneumool immunogeniity ssys. Some uthors re ffilite with GSK n GSK sponsore the stuy. Funing: The uthors hve no funing or support to report. however it shoul e note tht "The lortory of DG n MZ reeives grnt support from GSK n DG ts s n osionl onsultnt to GSK. This oes not lter the uthors' herene to PLOS ONE poliies on shring t n mterils. All other uthors elre to hve no onflits of interests." UNCLEAR: not muh info to evlute UNCLEAR: not muh info to evlute UNCLEAR: not enough info to evlute

7 2203 Blok, 2015 Overll, 751 helthy infnts (ge: ys) were rn- omize to reeive 3 or 4 oses of MenACWY-CRM (2/4/12 or 2/4/6/12 months of ge, respetively) with + routine vintions (ACWY3 n ACWY4 groups, respetively) or + routine vintions only (routine group) Results of Phse 3, Rnomize, Open-lel Tril 456 Anrews, 2014 e referene for not ville e referene for not ville 734 Prymul, 2013 This is follow-up to n erlier stuy tht rnomize hilren to PCV10 primry series vintion or to ontrol group. However, hilren in the ontrol group were not rnomize Wysoki, 2015 f While the stuy h 3 groups given ifferent vine sheules, hilrens' ssignment into group ws se on their ge, not rnomiztion Silfverl, 2011 f Of the 351 hilren vinte in the previous primry/ ooster stuy, 110 (from 2 of the 4 ountries in tht stuy) were enrolle in the present follow-up stuy, tht is, 51 in the PHiD-CV 2 1v n 59 in the PHiD-CV 3 1v group. A totl of 62 unprime, ge-mthe ontrols were lso enrolle in this fol- low-up stuy. Figure 1 shows resons for exlusion n the numer of hilren inlue in the ATP immunogeniity ohort per group. The stuy groups in the ATP immunogeniity ohort were omprle with respet to emogrphi hrteristis (Tle 2); tht is, ge t the time of ministrtion of the PHiD- CV ose rnge from 38 to 40 months ross groups, gener istriu- tion (40% 52% girls ross groups), n ethniity (95% 100% white Cusin or Europen heritge ross groups) Outol, 2014 "120 hilren wre rnomize (1:1) to reeive " 2419 Diko, 2015 f Chilren were not truly rnomize in this stuy- "The stuy popultion onsiste of PHiD-CV unprime Mlin hilren previously enrolle in the ontrol group of stuy NCT reeiving 2-ose th-up vintion with PHiD-CV in the seon yer of life." This phse III, open-lel, ontrolle stuy (NCT ) ws onute in 9 helth entres "This ws phse 3, openlel, multienter stuy" This long-term follow-up (111736/NCT ) of pre- vious primry/ooster vintion stuy12 h n open ontrolle esign n inlue hilren from 2 Sweish n 5 Slovkin primry re enters in the perio Deemer 2008 to July "In ths phse II, oserverline stuy" "This phse III, open-lel stuy" All serologil nlyses were performe y stff line to vine group ssignment. referene for stuy not ville Overll, 571 (75%) enrolle sujets omplete the stuy. referene for stuy not ville Not stte Aoring to Figure 2, only 62.5% of the totl vinte ohort from the previous stuy tht were eligile to prtiipte in this stuy were inlue in the ATP immunogeniity ohort. Not stte Aoring to Figure 1, 99.1% of the 355 enrolle hilren were inlue for nlysis. not stte 97% of hilren enrolle in stuy inlue in nlysis ISPPD strt oes not stte 120 hilren were rnomize, ut the tles presenting results re too lurry to mke out. This strt oul not e foun through n online serh. Not stte Aoring to Figure 1, 75.6% of the 78 hilren in the ohort of unprime sujets were inlue for nlysis. Novrtis Vines n Dignostis, In. provie finnil support for the onut of the reserh, inluing stuy esign s well s t olletion, nlysis n interprettion, n pi ll osts ssoite with the mnusript evelopment. L.H. n I.S. were employees of Novrtis group ompnies n hel stok ownership from the sponsoring ompny t the time of the stuy ut re now employees of GlxoSmithKline group ompnies. F.X. ws ontrtor ssoite t Novrtis Vines n Dignostis, In. ut is now ontrtor ssoite t GlxoSmithKline LLC, Unite Sttes. P.M.D. ws permnent employee of Novrtis Vines n some of the uthors n institutions hve reeive funing from inustry Some uthors re ffilite with GSK n GSK sponsore n onute prts of the stuy. Some uthors re ffilite with Pfizer, n Wyeth sponsore the stuy. GSK involve in stuy onut n esign One uthor is ffilite with GSK, n GSK provie funing. Some uthors re ffilite Smll smple size n=59 with GSK n GSK sponsore n onute prts of the stuy. UNCLEAR: not enough t on soure of immunogeniity results on UNCLEAR: nnot evlute ompleteness of t, limite info from strt

8 PRIME: IPD Cse Control Risk of Bis Tool Question Representtiveness of ses Seletion of Controls Definition of Controls Potentil onfouners mesure n juste for in the nlysis Asertinment of exposure Sme metho of sertinment for ses n ontrols? 7 Other Risk of Bis Answer Choie ) onseutive or oviously representtive series of ses ) potentil for seletion ises or not stte ) Unler ) Not stte/full text not ville (ie. Post or strt) ) ommunity ontrols ) hospitl ontrols ) test-negtive ontrols (e.g. non-vine type ses) ) no esription e) Unler f) Not stte/full text not ville (ie. Post or strt) ) no history of isese (enpoint) ) no esription of soure ) Unler ) Not stte/full text not ville (ie. Post or strt) Plese list out ftors tht were ontrolle for in the nlysis ) seure reor (eg provier history; immuniztion registry) ) prent/gurin written reor ) prent/gurin verl reor ) no esription e) Unler f) Not stte/full text not ville (ie. Post or strt) ) yes ) no ) Unler ) Not stte/full text not ville (ie. Post or strt) Plese omment on other ftors tht my introue is

9 RefID Referene (Country, Author, Yer) South Afri, von Gotterg, 2016 Quee Cn, Deeunink, 2015 Q1re p_ns Q1rep_Comments ses ientifie through ntionl lortoryse surveillne Prents of hilren with lortoryonfirme ses were ontte n invite to prtiipte. Brzil, Domingues, 2014 Q2se lon_ ns Q2selont_omments mthe hospitl ontrols sought Tle 1 illustrtes tht the ontrols i not hve the IPD serotypes ontrols otine from ntionl irth registry Q3e font _ns Q3efon_omments one n infer tht the ontrols re those with no history of the iseese, ut it oes not stte it expliitly Tle 1 illustrtes tht the ontrols i not hve the IPD serotypes one n infer tht the ontrols re those with no history of the iseese, ut it oes not stte it expliitly Q4onf_ ns Q5 ser exp _ns Q5serexp_omments Q6s mem eth_ ns Q6smemeth_omments Q7othis_omments PICO I & PICO II Assessment of Bis Q4onf_omments This is poster, so etile informtion is not ville. However, the tles stte tht moels were juste for whether the ptient h reeive 3 oses of pt vine t 16 weeks n presene of rowing in the home for HIVuninfete hilren. Moels were lso juste for reeipt of ntiretrovirl tretment n presene of severe immunosuppression on CD4+ T ell ount for HIV-infete hilren. Other moels were juste for mlnutrition n mternl eution s well for HIVuninfete hilren. Other moels for HIVinfete hilren were juste for reeipt of trimethoprim-sulfmethoxzole prophlxis. lortory-se surveillne mthe hospitl ontrols sought HIGH juste for ge, yer, seson, n unerlying meil onition (ny inition for 4th ose, inluing severe premturity, or sthm) lortory-onfirme IPD ses Some moels juste for reeipt of t lest one ose of tetrvlent iphtheri-tetnus-pertussis- Hemophilus influenz type B vine n ny hroni illness. lortory-se surveillne Telephone ontt for voluntry prtiiption until the numer of neessry ontrols ws rehe ses were ientifie from tive lortory-se surveillnet prtiipting hospitls n referene lortories. Controls were ientifie from ntionl irth registry. HIGH 456 UK, Anrews, 2014 (iniret ohort stuy) 2199 Verni et l "To ssess vine effetiveness, we use ll ses of invsive pneumool isese in the ohort eligile for vintion in Engln, Wles, n Northern Ireln ientifie up to Ot 31, 2013, through enhne ntionl surveillne y Puli Helth Engln"." ses were ientifie through lortoryse surveillne in 10 sttes in Brzil from Mrh 2010 to Deemer Cses were efine s S. pneumonie etete from normlly sterile site (e.g., loo or ererospinl flui) in hil ge-eligile to reeive 1 PCV10 ose. Initilly ses were ientifie y ulture only; however strting in Deemer 2010, some stuy sites etete ses using polymerse hin retion (PCR). Pneumool isoltes sumitte to Brzil s ntionl referene lortory were serotype using the Quellung re- tion; ses etete y non-ulture methos were serotype y PCR Iniret ohort stuy esign- "... ontrols re iniviuls with invsive pneumool isese use y the non- serotypes" For eh enrolle se, we ime to enrol four gemthe n neighourhoomthe ontrols. Potentil ontrols were sought through the Informtion System for Live Births, ntionl irth registry (with >95% of ll irths registere)12 tht lso inlue ll the ses. A list ws generte of hilren orn up to 1 month efore or fter the te of irth of the se n registere in the sme neighourhoo in whih the se resie t the time of illness. Iniret ohort stuy esign- "... ontrols re iniviuls with invsive pneumool isese use y the non- serotypes" euse the hoie of the ontrols using the ntionl registry whih lso inlue those who oul lter on eome ses, the efinition of wht they etermine ontrol is unler. ge, yer of infetion, linil risk group/omoriities, numer & timing of oses oring to tle 2 the following re the onfouners juste for: Ajuste for te of mission/meil ttention, ge t illness, y re ttenne n reeipt of t lest one iphtheri tetnus pertussis vine ose. "We otine vintion history... from generl prtitioners through postl questionnire n telephone lls." Vintion histories were strte from se-ptients immuniztion rs Iniret ohort stuy esign- "... seontrol esign wherein the ses re iniviuls with vinetype invsive pneumool isese n ontrols re iniviuls with invsive pneumool isese use y the non- serotypes" Cses n ontrols were enrolle in the stuy irrespetive of whether vine reors were ville. The primry soure of vintion history t ws the hil's immunistion r, otine from the prent or gurin. If these rs were not ville, the vintion history ws sought t the immunistion post where the hil ws vinte. : It shoul e note for this pper the methos were mentione in nother pper: here is the informiton for tht pper Effetiveness of ten-vlent pneumool onjugte vine ginst invsive pneumool isese in Brzil: mthe seontrol stuy. Lnet Respir Me Aurnen et l not stte s this is n strt f 3624 Pkistn, Ali, 2016 poster, not stte e 3646 Dominin Repuli, Tomzyk, 2016 poster, not stte e strt thus the seletion of ontrols not stte Controls re mthe on ge, thment, n seson, no mention of where they were reruite poster, efinition not stte ontrols re mthe on ge n neighorhoo, no mention of where they were reruite strt thus the efinition of ontrols not stte N/A N/A ulture onfirme serotype speifi ip ses retrive from ntionl infetious isese register strt thus the metho of sertinment for ses n ontrols UNCLEAR ompritive nlysis is one yet, stuy is ongoing f not stte poster, not stte UNCLEAR no history of isese in the prior month weight-for-ge z sore n home uilt of woo soure of immuniztion sttus not provie poster, not stte UNCLEAR

10 Guevr_2016.pf (IDC) Refi 17 Vn er Linen et l 2016.pf Cses of IPD were ientifie through the tive lor- tory-se surveillne. IPD ws efine s isoltion, PCR or ntigen etetion of Streptoous pneumonie from normlly sterile oy site. The Germn Ntionl Referene Center for Streptooi (GNRCS) hs onute surveillne for IPD in Germny sine 1992, using lortory-se pproh. IPD ses were efine s Streptoous pneumonie isoltes from loo, ererospinl flui (CSF) or ny other normlly sterile oy flui. Miroiologil ignosti lortories from ll over Germny hve een sening isoltes of IPD ses to the GNRCS on voluntry sis. In totl, over 400 lortories hve prtiipte, inluing lrge, ntionllyoperting ommeril ls. Prtiipting lor- tories re lote in ll Germn feerl sttes, n the numer of lortories per feerl stte orreltes to the ifferent popultion ensities of the sttes. eight ontrols were selete from hilren with no previous IPD, iniviully mthe y peitri prtie, istrit of resiene n te of irth (±2 months). Of ll the hilren who met these eligiility riteri, the eight with tes of irth losest to tht of the se were selete. Previous inlusion of twin ws n exlusion riterion. This stuy ws one on ohort of inhitnts of region of Nvrr This stuy esries the effets of the introution of hilhoo pneumool onjugte vintion on invsive pneumool isese mong hilren n ults in Germny, fous- ing on the ynmis of serotype istriutions in vinte n non-vinte ge groups over perio of 22 yers. no previous IPD, iniviully mthe y peitri prtie, Cox regression juste for ge s unerlying time sle, sex n vrile tht omines time perios n vintion sttus in tle 3. Conitionl logisti regression juste for sex n prentl inome level in tle 5 This stuy esries the effets of the introution of hilhoo pneumool onjugte vintion on invsive pneumool isese mong hilren n ults in Germny, fous- ing on the ynmis of serotype istriutions in vinte n non-vinte ge groups over perio of 22 yers. N/A N/A The Nvrr Helth Servie provies helthre, free t point of servie, to 97% of the inhitnts of the region. Clinil reors hve een omputerise sine 2000 n inlue reports from primry re, hospitl missions, the regionl vintion register, n lortory test results. Vintion history ws otine from the regionl v- intion register [23], whih inlues ll oses reeive y hilren, inluing those quire in the privte mrket. "A se ontrol stuy, neste within the ohort" inites tht the unerlying ohorts whih is me up of the ses/ ontrols the informtion olletion metho is the sme no esription s to the metho they got the vintion history for the iniviuls just the following "Cses were groupe per pneumool seson (from July to June of onseutive yers) euse of known infetion lusters uring winter. For the nlysis of vintion effets, we efine three time perios. The previntion perio from summrizes 9 pneumool sesons in whih hilren were not vinte (for ults: , 14 sesons). The seson ws onsiere trnsition yer in whih pneumool onjugte vintion ws introue, n ws tken out of the nlysis. The erly vintion perio summrize the three sesons ( , n ) in whih PCV7 ws use, n the lte vintion perio summrizes four sesons ( , , not stte UNCLEAR (in_ohort)miller pf Cses were tegorise into those eligile to reeive one or more priming oses of t 2 or 4 months n ge etween 2.5 n 13 months t time of infetion n those eligile for the 13 month ooster ose who h reeive oses of either PCV7 n /or t 2 n 4 months n were ge etween 13 n 23.9 months t time of infetion. Only ses with serotype n known vintion history were inlue in the nlysis. We use t from ntionwie surveillne progrm of IPD for hilren <16 yers se on ses ientifie y the Germn pei- tri surveillne unit ( Erheungseinheit für seltene päitrishe Erkrnkungen [ESPED] ). Inlusion riteri were: IPD ses in hil- ren months of ge mitte to Germn peitri hospitl from to (in_ohort)weiner with informtion on serotype n ger-2016.pf vintion sttus ville. (IDC)Knol Netherlns EID 2015.pf Also use of the iniret ohort metho utomtilly ontrols for ises in sertinment etween ses (i.e. those with vine serotype) n ontrols (i.e. those with nonvine serotype) s the infeting serotype is unknown t the time of ignosti investigtion n susequent reporting to our surveillne system Among the ses with non serotypes (ontrol group, N = 115) uptke of t lest one ose ws 80%, of t lest two oses ws 74% n of three oses 60% y the ge of 10 months. Among ses with serotypes inlue in, 38% h reeive t lest one ose, 32% t lest two oses n 30% three oses. Also use of the iniret ohort metho utomtilly ontrols for ises in sertinment etween ses (i.e. those with vine serotype) n ontrols (i.e. those with non-vine serotype) s the infet- ing serotype is unknown t the time of ignosti investigtion n susequent reporting to our surveillne system N/A N/A Among the ses with non serotypes (ontrol group, N = 115) uptke of t lest one ose ws 80%, of t lest two oses ws 74% n of three oses 60% y the ge of 10 months. Among ses with serotypes inlue in, 38% h reeive t lest one ose, 32% t lest two oses n 30% three oses. yer of infetion, ge in months juste for yer of infetion (2010, 2011, 2012, 2013 n 2014) to ount for potentil her effets n for ge in months to ount for ge speifi serotype vrition in IPD risk. Vintion histories were otine for ll ses y telephoning the Generl Prtitioner n otining tes n th numers of ny PCV7 or oses given n, for vineeligile hilren with no reor of hving reeive ny PCV oses, requesting resons for filure to vinte. Written onfirmtion of informtion provie y telephone ws otine. We use t from ntionwie surveillne progrm of IPD for hilren <16 yers se on ses ientifie y the Germn pei- tri surveillne unit ( Erheungseinheit für seltene päitrishe Erkrnkungen [ESPED] ). Inlusion riteri were: IPD ses in hil- ren months of ge mitte to Germn peitri hospitl from to with informtion on serotype n vintion sttus ville. A hil ws onsiere s vinte 14 ys fter the first ose. Vintion histories were otine for ll ses y telephoning the Generl Prtitioner n otining tes n th numers of ny PCV7 or oses given n, for vine- eligile hilren with no reor of hving reeive ny PCV oses, requesting resons for filure to vinte. Written onfirmtion of informtion provie y telephone ws otine. We use t from ntionwie surveillne progrm of IPD for hilren <16 yers se on ses ientifie y the Germn pei- tri surveillne unit ( Erheungseinheit für seltene päitrishe Erkrnkungen [ESPED] ). Inlusion riteri were: IPD ses in hil- ren months of ge mitte to Germn peitri hospitl from to with informtion on serotype n vintion sttus ville. A hil ws onsiere s vinte 14 ys fter the first ose. RW n MI report no ompeting interests. ML hs een memer of visory ors for n hs reeive speker honorri from Pfizer, GSK, Merk n SnofiPsteurMSD. Rvk ws supporte y grnt from Pfizer Phrm GmH. UNCLEAR

11 PRIME: IPD Pre Post Risk of Bis Assessment Tool Question Ws the outome mesure onsistently ross the stuy perio (e.g. surveillne methoology hnges; ws % ll IPD ses serotype onsistent pre n post) Does the surveillne initition prete the time perio use s seline (i.e. i the t olletion strt efore the stuy seline perio?) Di the sttistil methos exmine hnges in outome mesures from efore to fter the intervention? Were sttistil tests one tht provie p vlues for the pre to post hnges? Were the outome mesures of interest tken multiple times efore the intervention? ( ex. were multiple time points reporte for the seline perio; ws seline verge for more thn one yer?) Were the outome mesures of interest tken multiple times fter the intervention ( ex. were multiple time points reporte for the postintervention perio; ws post-intervention perio verge for more thn one yer?) Ws inustry (i.e., GSK or Pfizer) involve in this stuy? 7 Other risk of is Answers. Yes. No. Unler. Not stte/full text not ville (ie. Poster or strt). Yes. No. Unler. Not stte/full text not ville (ie. Poster or strt). Yes. No. Unler. Not stte/full text not ville (ie. Poster or strt). Yes. No. Unler. Not stte/full text not ville (ie. Poster or strt). Yes. No. Unler. Not stte/full text not ville (ie. Poster or strt). Yes. No. Unler. Not stte/full text not ville (ie. Poster or strt) Comments

12 PICO I/ PICO II RefID Referene (Country, Author,Yer) Q1onsis_ns Q1onsis_omments Q2se_ns Q2se_omments Q3prepost_ns Q3prepost_omments Q4efore_ns Q4efore_omments Q5fter_ns Q5fter_omments Q6inustry_ns Q6inustry_omments Q7othis_omments Overll Assessment 63 Finln, Jokinen, UK, Wight, Denmrk, Hroe Netherlns, Knol, ISPPD Isrel, Regev-Yohy, 2016 serotypes ville on >96% of notifie ses 50% missing serotype t in 2001/02 n only <10% missing serotype t fter intro. Also in 2010, reporting not stte in full eme mntory, text, ut voluntry efore then it ws reporting system voluntry. efore 2010 All IPD isoltes Authors mention routinely serotype, serotype speifi ntionl referene t from 1993 l t SSI onwrs iniret popultion: sentinel surveillne overing 25% of popultion, iret popultion: ntionl peitri l surveillne. All surveillne isoltes were pretes stuy y serotype y the 1 yer, not stte ntionl referene for ult sentinel l surveillne ll ls performing loo ultures in ountry provie ll isoltes surveillne system NIDR sine % Cis provie 2 referene ohorts, eh spnning 3 yers 95% Cis provie for PCV7- omp verge of 7 yers IRR with 95% Cis provie 8 yers pre-pcv t IRR with 95% Cis provie for serotype groups n 19A 2 yers pre-pcv7 reporte IRR only given for overll IPD, not VT IPD no pre-pcv7 t 1 trget ohort spnning 3 yers 1 yer for t, ut 2 yers for PCV7 t 3 yers for PCV7 n 3 yers for 2 yers for PCV7 n perios eh, more yers shown on grph Ntionl Institute for Helth n Welfre reeive funing from GSK for FinIP tril Puli Helth Engln is funer stuy fune y SSI whih oes not proue PCVs Ntionl Institute for Puli Helth n the Environment 2 yers for PCV7 perio n 4 yers of IAIPD Group Prtiipnts in FinIP were exlue from the iniret effets group, referene ohorts i not overlp with FinIP tril yers Authors ttempte to orret for missing ge n serotype t High Authors moele for yli vrition in serotype prevlene Very low iniene of 6A n 6C isese, my not e powere to etet ifferenes Cpture-repture metho ssure reporting of >95% ses 3672 Finln, Nuorti, Ireln, Cororn, Austrli, Jysinghe, Ben-Shimol( 2015) 326 Ben-Shimol et l No 428 Von Gotterg 2014 ll linil ls sumit Spn isoltes to THL for serotyping no informtion on the soure of the isoltes n ompleteness of reporting % isoltes serotypes not stte The proportion of isoltes for whih serotype ws etermine inrese from 40% to 70% in the perio etween July 2004 n June 2009 to >95% sine July 2009 to Deemer The proportion To evlute of isoltes Lortory-se for whih surveillne NIDR in ple sine 1995 surveillne ommene in April of 1st yer just IR reporte "onstnt n onsistent pture of isoltes sine 2002" the first yer of stuy surveillne initite Our t in erive 1989 from Lortory-se n ongoing surveillne for uthors stte tht hnges were signifint ut o not provie p-vlues or Cis 4 yers pre-pcv 4 yers of PCV10 IRR with 95% CI provie IRR with 95% Cis provie Iniene rte rtios (IRR) The ifferene n 95% in rtes n the 1 yer of pre-pcv t 3 yers of pre-pcv t 6 yers pre-pcv7 t men n stnr evitions verge rte re for perio yers of PCV7 n 5 yers of 5 yers of PCV7 n 3 yers of 2 yer post PCV7, 1 yer only h post 1 yer of informtion The 7-vlent for pneumool THL n Univ of Tmpere prtly fune y Pfizer Ireln NCIRS fune y govt ept of hetlh Isreli n Peitri n Bteremi n Meningitis Isreli Peitri Group Bteremi Dr. von Gotterg n reports reeiving grnt Exlue yers of FinIP tril n trnsition yer unler wht % of ll isoltes this stuy represents Ajuste for missing serotype t High

13 525 Steens Diwr et l Port et l. Vine Lepoutre 2015 oservtionlretrospetive popultion stuy; routine olletion of serotype speifi t in MSIS strte in For 2004, 2004, n 2006, serotype speifi t ws linke to notifie t from MSIS retrospetively. Ntionl l surveillne Serotyping of Sp6A n Sp6B ws Sine 2001, pneumool strins isolte from CSF (meningitis) n from loo in hilren (0 15 yers of ge) re ollete from hospitllortories n sent to the NRCP y 22 regionl lortories orgnize into pneumool surveillne regionl sheme (Oservtoires Régionux es Pneumooques). In ition systemti 1/6 smple of pneumool isoltes isolte from loo in ults (>15 yers) re ollete n sent to the NRCP y the Surveillne strte in Jn 2004 n PCV7 ws introue in July 2006 surveillne strte in 2007 n ws introue in 2010 IRR with 05% Cis provie solute n reltive risk reution with 95% Cis Surveillne strte in July 1999 IRR with 95% Cis Three perios were efine oring to the tes of the introution of PCV7 n in the Frenh immuniztion sheule: pre PCV7 perio ( ), lte PCV7 perio ( ) orresponing to the lst yers of PCV7 exlusive use in Frne, n post perio (2012), two yers fter introution. Iniene rte rtios (IRR) were ompute for ll types-, n speifi serotypes-groups IPD etween perios, onfiene intervls for iniene rte rtios were ompute using the ohort stuy risk lultor ommn of Stt Iniene rtes were ompre etween the perios y Fisher ext test. The signifine level ws set t Perent hnge in the iniene of IPD etween perios ws ompute s (IRR-1) 100. The nlysis ws one with STATA 12.1 (SttCorp ). 2 yers pre PCVC7 t pre- iniene verge for pre-pcv7 verge for initilly they o not mention tht the IR re men vlues, however in tle 1 they mention tht they hve liste the men numer of ses/yer for prepv perio n this is where they oul hve lulte the IR vlues from 4 yers for PCV7 t n 1 yer post t 1 yer post efore the trnsition to PCV10; 3 yers post 2 yers PCV10 post PCV7 n 3 yers post sine there is the sme situiton in Post PCV7 perio, it is unler s to whether it is men numers Conute y meil miroiologil lortoriesn linins in Norwy This work ws supporte y n unrestrite, investigtor initite grnt from Pfizer. The uthors oneive the stuy n the stuy esign ws evelope n gree to y the uthors without ny input from the funing oy. This work ws prtilly supporte y grnt A. Lepoutre elres no potentil onflits of interest, E. Vron reeive fees from Pfizer n GlxoSmithKline for prtiiption in working groups on pneumool vines, S. Georges, F. Dorléns, C. Jnoir, L. Gutmnn n D. Lévy-Bruhl elre no potentil on- flits of interest. iniene rte reutions in hilren of >2-5 yers ws no oserve. The vintion progrm ws not fully implemente in ll Moron hilren. In ft, in Ot 2010 only hilren less thn or equl to 2 montsh were inlue in the vine progrm.