A Phase 3, Open-Label, Randomized Trial to Investigate the Immunogenicity and Safety of the Co-administration of a Subcutaneous Dengue Tetravalent Vaccine (Live, Attenuated) (TDV) and an Intramuscular Recombinant 9-Valent Human Papillomavirus (9vHPV) Vaccine in Subjects Aged ≥9 to <15 Years in an Endemic Country for Dengue
Phase: PHASE3
Conditions: Dengue Fever
Sponsor: Takeda



 
 
P R O T O C O L  
A P hase 3, O pe n -La bel, Ra n d o mize d Trial t o I n v esti gate t h e I m m u n o ge ni cit y a n d Safet y of t he 
C o -a d mi nistrati o n of a S u bc uta ne o us D e n g ue Tetra vale nt Vacci n e ( Li ve, Atte n uate d) ( T D V) a n d 
a n I ntra m usc ular Rec o m bi na nt 9 -Vale nt H u ma n Pa pill o ma vir us ( 9 v H P V ) Vacci n e i n S u bjects 
A ge d ≥9 t o < 1 5 Years i n a n E n de mic C o u ntr y f or De n g ue  
I m m u n o ge nicit y a n d S afet y of T D V a n d 9 v H P V i n S u bjects A ge d ≥9 t o < 1 5 Ye ars  
S p o ns or:  
Ta ke da V acci nes, I nc.  
4 0 La n ds d o w ne Street  
Ca m bri d ge, M A, 0 2 1 3 9  
U S A  
Tri al I de ntifier:  
D E N -3 0 8  
I N D N u m ber: 
N ot A p plica ble  
E u dr a C T N u m ber:  
N ot A p plica ble  
Tri al V acci ne N a me:  
I nvesti g ati o n al v acci ne 
De n g ue Tetra val e nt Vacci ne ( Li v e Atte n uat e d) ( T D V) c o m prise d of a 
m olec ularl y c haract erize d, atte n uate d de n g u e ser ot y pe 2 strai n ( T D V -2), 
a de n g u e ser ot y pes 2/ 1 rec o m bi na nt strai n ( T D V -1), a de n g u e ser ot y pes 
2/ 3 rec o m bi na nt strai n ( T D V -3), a n d a de n g u e ser ot y pes 2/ 4 
rec o m bi na nt strai n ( T D V-4) . 
C o nc o mit a nt v acci ne  
R ec o m bi na nt 9 -Vale nt H u ma n Pa pill o ma vir us ( 9 v H P V ) vacci ne 
c o ntai ni n g t he L 1 pr otei ns f or H P V t y p es 6, 1 1, 1 6, 1 8, 3 1, 3 3, 4 5, 5 2, 
a n d 5 8. 
T a ke d a A p pr o v al D ate:  0 3  Marc h  2 0 2 1  
Versi o n:  
Versi o n 5 . 0 
C O N FI D E N TI A L P R O P E R T Y O F T A K E D A  
T his d oc u me nt is a c o nfi de ntial c o m m u nicati o n of T a ke da. Acce pta nce of t his d oc u me nt c o nstit utes t he a gree me nt b y 
t he reci pie nt t hat n o i nf or mati o n c o ntai ne d herei n will be p u blis he d or discl ose d wit h o ut writte n a ut h orizati o n fr o m 
T a ke d a e xce pt t o t he e xte nt ne cessar y t o o bt ai n i nf or me d c o nse nt or i nf or me d c o nse nt a n d p e diatric asse nt fr o m t h ose 
pers o ns t o w h o m t he i n vesti gati o nal pr o d uct ma y be a d mi nistere d or t heir le gall y acce pta ble re prese ntati ves. 
F urt her m ore, t he i nf or mati o n is o nl y mea nt f or re vie w a n d c o m plia nce b y t h e reci pie nt, his or her staff, a n d a p plica ble 
i nstit uti o nal re vie w c o m mittees, a n d re g ulat or y a ge ncies t o e na ble c o n d uct of t he trial. 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 2  of 8 7  
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0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
1. 0  
A D MI NI S T R A TI V E I N F O R M A TI O N  
1. 1  
C o nt acts  
Iss ue 
C o nt act  
Seri o us a d verse e ve nt a n d pre g na nc y 
re p orti n g 
  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
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C O N FI D E N TI A L  
 
1. 2  
A p pr o v al  
R E P R E S E N T A TI V E S O F T A K E D A  
T his trial will be c o n d ucte d wit h t he hi g h est res pect f or t he i n di vi d ual parti ci pa nts i n acc or da nce 
wit h t he  re q uire me nts of t his cli nical trial pr ot oc ol a n d als o i n acc or da n ce wit h t he f oll o wi n g: 
•  T he et hical pri nci ples t h at ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki [ 1 ]. 
•  I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or P har mace uticals f or 
H u ma n Use (I C H), E 6 ( R 2) G o o d cli nical practice ( G C P): C o nse ns us g ui d eli ne [ 2 ]. 
•  All a p plica ble la ws a n d re g ul ati o ns, i ncl u di n g, b ut n ot li mite d t o t h ose relate d t o data pri vac y 
a n d cli nical trial discl os ure.  
SI G N A T U R E S  
{ See a p pe n de d si g n at ure p a ge} 
 
 
{ See a p pe n de d si gn at ure p a ge}  
 
Date   
Date  
{ See a p pe n de d si g n at ure p a ge} 
 
 
{ See a p pe n de d si g n at ure p a ge} 
 
Date   
Date  
  
  
  
  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 4  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
I N V E S TI G A T O R A G R E E M E N T 
I c o nfir m t hat I ha v e rea d a n d t hat I u n dersta n d t his pr ot oc ol, t he i n vesti gat or’s br oc h ure (I B), a n d 
a n y ot h er pr o d u ct i nf or m ati o n pr o vi de d b y t h e s p o ns or. I a gree t o c o n d u ct t his trial i n acc or da n ce 
wit h t he re q uire me nts of t his pr ot oc ol a n d pr otect t he ri g hts, s afet y, pri vac y, a n d well -bei n g of tri al 
s u bjects i n acc or da nce wit h t he f oll o wi n g: 
•  T he et hical pri nci ples t h at ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki [1 ]. 
•  I C H E 6 ( R 2), G C P: C o nse ns us g ui deli ne [2 ]. 
•  All a p plica ble la ws a n d  re g ul ati o ns, i ncl u di n g, b ut n ot li mite d t o t h ose relate d t o data pri vac y 
a n d cli nical trial discl os ure.  
•  Re g ulat or y re q uire m e nts f or re p orti n g seri o us a d verse e ve nts ( S A Es) d efi ne d i n Secti o n  1 0. 4. 4  
of t his pr ot oc ol.  
•  Ter ms o utli ne d i n t he Cli nical Trial Site A gree me nt.  
•  A p pe n di x  A  –  Res p o nsi bilities of t he i n vesti gat or.  
I f urt her a ut h orize t hat m y pers o nal i nf or mati o n m a y b e pr ocesse d a n d tra nsferre d i n acc or da n ce 
wit h t he uses c o nte m plat e d i n A p pe n di x  B  of t his pr ot oc ol.  
 
 
Si g nat ure of I n vesti gat or  
Date  
 
 
I n v esti gat or Na me ( pri nt or t y pe) 
 
 
 
I n v esti gat or’s Title 
 
 
 
L ocati o n of Facilit y ( Cit y, State)  
 
 
 
L ocati o n of Facilit y ( C o u ntr y)  
 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 5  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
1. 3  
Pr ot oc ol V ersi o n S u m m ar y of C h a n ges  
T his d oc u me nt descri bes t he c ha n ges i n refere nce t o t he pr ot oc ol i nc or p orati n g A me n d me nt N o.  2 
( Versi o n 4 ). 
1. 3. 1  Versi o n  Hist or y  
D ate  
Versi o n N u m ber  
C h a n ge T y pe  
Re gi o n  
0 9 J ul y 2 0 1 8  
1. 0 (i nter nal)  
N ot a p plica ble  
Gl o bal  
0 2 Dece m ber 2 0 1 9  
2. 0 (i nitial pr ot oc ol)  
N ot a p plica ble  
Gl o bal  
1 0 A u g ust 2 0 2 0  
3. 0 (a me n d me nt 1)  
N o n -s u bsta ntial 
Gl o bal  
0 3 Marc h 2 0 2 1  
4 . 0 (i nter nal) 
N ot a p plica ble  
Gl o bal  
0 3 Marc h 2 0 2 1  
5 . 0 (a me n d me nt 2) 
S u bsta ntial  
Gl o bal  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
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Pr ot oc ol Versi o n 5 . 0 
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C O N FI D E N TI A L  
 
1. 3. 2  S u m m ar y of C h a n ges  
A me n d me nt t o Pr ot oc ol Versi o n 3. 0, 1 0 A u g ust 2 0 2 0  
R ati o n ale f or t he a me n d me nt:  
T his pr ot oc ol a me n d me nt is t o a d d a clarificati o n t hat, d ue t o t he c or o na vir us disease 2 0 1 9 
( C O VI D-1 9) pa n de mic, alter nati ve m o nit ori n g a n d data verifi cati o n a p pr oac hes ma y b e use d.  
•  A d diti o n of a clarifi cati o n t hat s o me of t he test res ults ma y n ot be a v aila ble pri or t o data bas e 
l oc k beca us e s o me trial l a b orat or y pr oce d ures are n ot carrie d o ut d uri n g t he C O VI D-1 9 
pa n de mic.  
Ot her m o dificati o n s: 
•  T he f oll o wi n g m o dificati o ns were ma de f or ali g n me nt wit h pr ot oc ol te m plate Versi o n 4. 0:  
-  U p date i n res p o nsi bilities of t he si g n at or y i n vesti gat or.  
-  A d diti o n of trial ris k ma na ge me nt.  
•  A d mi nistrati ve c ha n ge of t he details of t he me dical direct or a n d cli nical pr oject o versi g ht 
ma na ger.  
•  Deleti o n of pr o p riet ar y ta ble s h o wi n g l o w er li mits of q ua ntificati o n a n d ser ostat us c ut-offs 
f or eac h of t he 9 v acci n e H P V t y pes. 
•  Fe w mi n or e dit orial c ha n ges.  
Details of t he c h a n ges are o utli ne d bel o w. I n t his secti o n o nl y (i e, n ot i n t he pr ot oc ol b o d y) all 
ne w te xt is s h o w n i n b ol d italics a n d a n y re d u n d a nt te xt is mar ke d usi n g stri ket hr o u g h.  
 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 7  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
Secti o n  
Descri pti o n of c h a n ge  
 
Title 
pa ge  
Date: 1 0 A u g ust 2 0 2 0  0 3  M arc h 2 0 2 1  
Versi o n 3. 0  5 . 0 
1. 2  
 
2. 0  a n d 
5. 2. 2  
Deleti o n of pr o priet ar y ta ble c o ntai ni n g l o w er li mits of q ua ntificati o n a n d s er ostat us 
c ut-offs f or eac h of t he 9 vacci ne H P V t y p es a n d cr oss referral t o t he statistical a nal ysis 
pla n a d de d i nstea d. 
T he l o wer li mits of q ua ntificati o n a n d ser ost at us c ut offs f or eac h of t he 9 v acci ne H P V 
t y pes are s h o w n b el o w. 
F or t he l o wer li mits of q u a ntific ati o n a n d ser ost at us c ut -offs f or e ac h of t he 9 
v acci ne H P V ty pes, ple ase refer t o t he st atistic al a n alysis pl a n ( S A P).  
2. 0  
Ha n dli n g of missi n g data will be descri be d i n t he statistical a nal ysis pla n ( S A P) S A P .  
2. 1  
Ta ble 2.a  
Sc he d ule of Trial Pr oce d ures ( Visits 1 t o 7 [ Da y 1 ( M 0) t o Da y 3 6 0 
( M 1 2)]) 
N ote: W he n a site visit c a n n ot be c arrie d o ut d ue t o t he c or o n avir us dise ase 2 0 1 9 
(C O VI D -1 9 ) p a n de mic, alt er n ative m et h o ds of c o nt act (e. g tele p h o ne c o nt act) will 
be m a de f or s u bjects w h o are still u n der m o nit ori n g f or s afety re p orti n g.  
  
  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 8  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
Secti o n  
Descri pti o n of c h a n ge  
 
3. 2  
T he s p o ns or will select a si g n at or y pri nci p al i n vesti gat or ( PI)/ c o or di nati n g i n vesti gat or 
fr o m t he i n v esti gat ors w h o partici pate i n t he trial. S electi o n criteria f or t his i n vesti gat or 
will i ncl u de si g nifica nt k n o wle d ge of t he tri al pr ot oc ol, t he i n vesti gati o nal vacci ne, 
t heir e x pertise i n t he t hera pe utic area a n d t he c o n d uct of cli nical res earc h as well as 
trial partici pati o n. T he si g nat or y PI/ c o or di nati n g i n vesti gat or will be re q uir e d t o 
re vie w a n d si g n t he cli nical st u d y re p ort a n d b y d oi n g s o a grees t hat it acc uratel y 
descri bes t he r es ults of t he trial.  
Selecti o n criteri a f or t he pri nci p al i nvesti g at or ( PI) will i ncl u de si g nific a nt 
k n o wle d ge of t he tri al pr ot oc ol, t he i nvesti g ati o n al v acci ne, t heir e x pertise i n t he 
t her a pe utic are a a n d t he c o n d uct of cli nic al rese arc h as well as tri al p artici p ati o n. 
T a ke d a will select a si g n at ory i nvesti g at or fr o m t he i nvesti g at ors w h o p artici p ate i n 
t he st u dy. T he si g n at ory i nvesti g at or will be re q uire d t o revie w a n d si g n t he cli nic al 
pr ot oc ol. T he si g n at ory i nvesti g at or will als o be re q uire d t o revie w a n d si g n t he 
cli nic al st u dy re p ort ( C S R) a n d by d oi n g s o a grees t h at it acc ur ately descri bes t he 
res ults of t he tri al. 
3. 3  
Q T L  
Q u ality t oler a nce li mits  
8. 4  
T o pre ve nt bias or t h e perce pti o n of bias, st u d y t ea m me m bers res p o nsi ble f or decisi o n 
ma ki n g re gar di n g st u d y c o n d uct or a nal ysis of dat a after t he first s u bject e nr oll me nt 
(e g pr ot o c ol de vi ati o n  re vie w, pr ot oc ol a me n d me nt a n d statistical a nal ysis pla n [ S A P] 
S A P  a me n d me nt) will be d oc u me nte d i n t he data access ma na ge me n t pla n, a n d will be 
i n de pe n de nt of u n bli n de d data re vie w. 
9. 1. 5  
B o d y te m perat ure me as ure me nt will be descri be d i n t he Pr oce d ures M a n ual.  
9. 3. 1  
Bl o o d s h o ul d be ta ke n fr o m t he s u bject usi n g a n ase ptic ve ni p u nct ure t ec h ni q ue f or 
ser ol o gi cal i m m u n o ge nicit y testi n g. Refer t o t he d etaile d c ollecti o n a n d h a n dli n g 
pr oce d ures o utli ne d i n t he Pr oce d ures Ma n uals.  
9. 3. 4  
Bl o o d s h o ul d be ta ke n fr o m t he s u bject usi n g a n ase ptic ve ni p u nct ure t ec h ni q ue f or 
ser ol o gi cal i m m u n o ge nicit y testi n g. Refer t o t he d etail e d c ollecti o n a n d h a n dli n g 
pr oce d ures o utli ne d i n t he Pr oce d ures Ma n uals.  
9. 3. 6  
N ot a p plica ble.  
W he n a site visit c a n n ot be c arrie d o ut d ue t o t he C O VI D -1 9 p a n de mic , alter n ative 
m et h o ds of c o nt act (e. g tele p h o ne c o nt act) will be m a de f or s u bjects w h o are still 
u n der m o nit ori n g f or s afety re p orti n g.  
1 2. 1  
W he n a site visit c a n n ot be c arrie d o ut d ue t o t he C O VI D -1 9 p a n de mic, alter n ative 
m et h o ds of c o nt act (e. g tele p h o ne c o nt act) will be m a de f or s u bjects w h o are still 
u n der m o nit ori n g f or s afety  re p orti n g. Refer als o t o Secti o n 1 4. 1 . 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 9  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
Secti o n  
Descri pti o n of c h a n ge  
 
1 4. 0  
1 4. 1 Tri al -S ite M o nit ori n g Visits 
I n t he eve nt a m o nit or c a n n ot visit t he site i n a ti m ely m a n ner d ue t o t he C O VI D -1 9 
p a n de mic, alter n ative m o nit ori n g a p pr o ac hes s uc h as re m ote s o urce d at a 
verific ati o n or tele p h o ne c o nt act m ay be use d t o e ns ure d at a q u ality a n d i nte gr ity 
a n d m ai nt ai n s u bject s afety. Alter n ative m o nit ori n g a p pr o ac hes s h o ul d be use d o nly 
w here all o we d by t he l oc al He alt h A ut h ority a n d w he n a p pr ove d by t he I R B/I E C. 
D uri n g re m ote m o nit ori n g, t he m o nit or s h o ul d f oc us o n tri al activities t h at are 
esse nti al t o t he s afety of tri al s u bjects a n d/ or d at a reli a bility.  
1 4. 4 Tri al Ris k M a n a ge m e nt  
T he I C H E 6 a d de n d u m ( R 2) g ui d a nce e nc o ur a ges a ris k -b ase d a p pr o ac h t o t he 
m a n a ge m e nt of cli nic al tri als a n d i ncl u des re q uire m e nts f or ris k c o ntr ol a n d ris k 
re p orti n g. T a ke d a or desi g nee est a blis he d q u ality toler a nce li mits ( Q T L) t a ki n g i nt o 
c o nsi der ati o n t he m e dic al a n d st atistic al c h ar acteristics of t he v ari a bles a n d t he 
st atistic al desi g n of t he tri al. T his pr ocess w as perf or m e d acc or di n g t o T a ke d a 
i nter n al pr oce d ures. 
At t he e n d of t he tri al, t he q u ality m a n a ge m e nt a p pr o ac h i m ple m e nte d will be 
descri be d i n t he C S R. If a p plic a ble, t he C S R will s u m m arize i m p ort a nt devi ati o ns 
fr o m t he pre defi ne d Q T L a n d t he re m e di al acti o ns t a ke n. 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 1 0  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
Secti o n  
Descri pti o n of c h a n ge  
 
1 6. 0  
2 . I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or 
P har mace uticals f or H u m a n Use (I C H). I C H har m o nise d g ui deli ne. I nte grat e d 
A d de n d u m t o I C H E 6 ( R 1): G ui deli ne f or G o o d Cli nical Practice I C H E 6 ( R 2): I C H 
C o nse ns us G ui deli ne. A vaila ble at htt ps:// w w w. f da. g o v/ me di a/ 9 3 8 8 4/ d o w nl oa d 
[ Accesse d 1 0 A u g ust 2 0 2 0  0 3  M arc h 2 0 2 1].  
7 . W orl d Healt h Or ga niz ati o n, 2 0 1 9. De n g u e a n d se vere d e n g ue. Fact S heet. A vaila ble 
at htt ps:// w w w. w h o.i nt/e n/ ne ws -r o o m/fact-s heets/ detail/ de n g u e-a n d -se vere-de n g ue 
[ Accesse d 1 0 A u g ust 2 0 2 0  0 3  M arc h 2 0 2 1].  
8 . W orl d Healt h Or ga niz ati o n, 1 9 9 7. De n g ue h e m orr ha gic fe ver: dia g n osis, treat me nt, 
pre ve nti o n a n d c o ntr ol, 2 n d E diti o n. Ge ne va. A vaila ble at 
htt p:// w w w. w h o.i nt/csr/res o urces/ p u blicati o ns/ de n g ue/ D e n g ue p u blicati o n/e n/ 
[ Accesse d 1 0 A u g ust 2 0 2 0  0 3  M arc h 2 0 2 1].  
9 . W orl d Healt h Or ga niz ati o n, 2 0 0 9. De n g ue g ui d eli nes f or dia g n osis, treat me nt, 
pre ve nti o n a n d c o ntr ol. A vaila ble at 
htt p:// w w w. w h o.i nt/t dr/ p u blicati o ns/ d oc u me nts/ de n g ue -dia g n osis. p df. [ Accesse d 1 0 
A u g ust 2 0 2 0  0 3  M arc h 2 0 2 1].  
1 4 . Re vise d S A G E rec o m me n dati o n o n use of de n g ue v acci ne. A pril 2 0 1 8. A vaila ble 
at 
htt ps:// w w w. w h o.i nt/i m m u nizati o n/ diseases/ de n g ue/r e vise d _ S A G E _rec o m me n dati o n
s _ de n g u e _ vacci nes _a pr 2 0 1 8/e n/ [ Accesse d 1 0 A u g ust 2 0 2 0  0 3  M arc h 2 0 2 1].  
1 5 . W orl d Healt h Or ga ni zati o n. Wee kl y E pi d e mi ol o gical Rec or d. 2 0 1 8. 9 3: 3 2 9-4 4. 
A vaila ble at htt p:// w w w. w h o.i nt/ wer [ Accesse d 1 0 A u g ust 2 0 2 0  0 3  M arc h 2 0 2 1].  
1 8 . W orl d Healt h Or ga ni zati o n. H u ma n pa pill o ma vir us ( H P V). A vaila ble at 
htt p:// w w w. w h o.i nt/i m m u nizati o n/ diseases/ h p v/e n/ [ Accesse d  1 0 A u g ust 2 0 2 0  0 3  
M arc h 2 0 2 1].  
1 9 . Merc k. G ar dasil 9 prescri bi n g i nf or mati o n. A vaila ble at 
htt ps:// w w w.f da. g o v/ me dia/ 9 0 0 6 4/ d o w nl oa d [ Accesse d 1 0 A u g ust 2 0 2 0  0 3  M arc h 
2 0 2 1].  
2 2 . P olic y a n d c o m m u nic ati o n b ulleti n –  T he cli nical c e nt er. G ui deli nes f or li mits of 
bl o o d dra w n f or researc h p ur p oses i n t he cli nical ce nter. Ma n u al tra ns mittal s heet, n o. 
M 9 5 -9 (re v.), 2 0 0 9. A vaila ble at 
htt ps://ir b.researc h.c h o p. e d u/sites/ defa ult/files/ d oc u me nts/ g _ ni h _ bl o o d dra ws. p df 
[ Accesse d 1 0 A u g ust 2 0 2 0  0 3  M arc h 2 0 2 1].  
 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 1 1  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
T A B L E O F C O N T E N T S  
1. 0  
A D MI NI S T R A TI V E I N F O R M A TI O N  ..............................................................................2  
1. 1  
C o ntacts ..........................................................................................................................2  
1. 2  
A p pr o val  ........................................................................................................................3  
1. 3  
Pr ot oc ol Versi o n S u m mar y of C ha n ges  .........................................................................5  
1. 3. 1  Versi o n Hist or y  ........................................................................................................5  
1. 3. 2  S u m mar y of C ha n ges  ...............................................................................................6  
2. 0  
T RI A L S U M M A R Y  ..........................................................................................................1 6  
2. 1  
Sc he d ule of Trial Pr oce d ures  .......................................................................................2 5  
3. 0  
T RI A L R E F E R E N C E I N F O R M A TI O N  ...........................................................................2 8  
3. 1  
Trial -Relate d Res p o nsi bilities  ......................................................................................2 8  
3. 2  
Pri nci pal I n v esti gat or/ C o or di nati n g I n v esti gat or  .........................................................2 8  
3. 3  
List of A b bre viati o ns  ...................................................................................................2 9  
3. 4  
C or p orate I d e ntificati o n  ...............................................................................................3 1  
4. 0  
I N T R O D U C TI O N .............................................................................................................3 2  
4. 1  
Bac k gr o u n d  ..................................................................................................................3 2  
4. 2  
Rati o nale f or t he Pr o p ose d Trial  ..................................................................................3 3  
5. 0  
T RI A L O BJ E C TI V E S A N D  E N D P OI N T S  ......................................................................3 5  
5. 1  
O bjecti ves  ....................................................................................................................3 5  
5. 1. 1  Pri mar y O bj ecti ve  ..................................................................................................3 5  
5. 1. 2  Sec o n dar y O bj ecti ves .............................................................................................3 5  
5. 2  
E n d p oi nts  .....................................................................................................................3 5  
5. 2. 1  Pri mar y E n d p oi nt  ...................................................................................................3 5  
5. 2. 2  Sec o n dar y E n d p oi nts  .............................................................................................3 5  
6. 0  
T RI A L D E SI G N A N D D E S C RI P TI O N  ...........................................................................3 7  
6. 1  
Trial Desi g n  .................................................................................................................3 7  
6. 2  
J ustificati o n f or Trial Desi g n, D ose, a n d E n d p oi nts ....................................................3 8  
6. 3  
Pla n ne d D urati o n of S u bject’s E x pecte d Partici pati o n i n t he E ntire Trial  ..................3 9  
6. 4  
Pre mat ure Ter mi nati o n or S us pe nsi o n of Trial or I n vesti gati o nal Site  .......................3 9  
6. 4. 1  Criter ia f or Pre m at ure T er mi nati o n or S us pe nsi o n of t he Trial .............................3 9  
6. 4. 2  Criteria f or Pre m at ure T er mi nati o n or S us pe nsi o n of I n vesti gati o nal Sites  ..........3 9  
6. 4. 3  Pr oce d ures f or Pre mat ure Ter mi nati o n or S us pe nsi o n of t he Trial or t he 
Partici pati o n of I n vesti gati o nal Site(s) ...................................................................4 0  
7. 0  
S E L E C TI O N A N D DI S C O N TI N U A TI O N/ WI T H D R A W A L  O F S U BJ E C T S  ...............4 1  
7. 1  
I n cl usi o n Criteria .........................................................................................................4 1  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 1 2  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
7. 2  
E x cl usi o n Criteria  ........................................................................................................4 1  
7. 3  
Criter ia f or Dela y of Trial Vacci ne A d mi nistrati o n at Da y 9 0 ( M 3) a n d Da y 1 8 0 
( M 6) i n Gr o u p 1, a n d D a y 1 8 0 ( M 6) i n Gr o u p 2 .........................................................4 3  
7. 4  
Criteria  f or E arl y Ter mi n ati o n of a S u bject’s Trial Partici pati o n ................................4 4  
7. 5  
Criteria f or Pre m at ure Disc o nti n uati o n of Trial Vacci ne A d mi nistrati o n  ...................4 5  
8. 0  
C LI NI C A L T RI A L M A T E R I A L M A N A G E M E N T .........................................................4 7  
8. 1  
Trial Vacci nes a n d M aterials  .......................................................................................4 7  
8. 1. 1  D osa ge F or m, Ma n ufact uri n g, Pac ka gi n g,  a n d La beli n g  ......................................4 7  
8. 1. 2  St ora ge  ...................................................................................................................4 8  
8. 1. 3  D ose a n d Re gi me n  .................................................................................................4 9  
8. 2  
Trial Vacci ne Assi g n me nt a n d Dis pe nsi n g Pr oce d ures  ...............................................4 9  
8. 2. 1  Preca uti o ns t o be O bser ve d W he n A d mi nisteri n g t he Trial Vacci ne(s)  ................5 0  
8. 3  
Ra n d o mizati o n C o de Creati o n a n d St ora ge  .................................................................5 0  
8. 4  
Trial Vacci ne Bli n d Mai nte na nce  ................................................................................5 0  
8. 5  
U n bli n di n g Pr oce d ure  ..................................................................................................5 0  
8. 6  
Acc o u nta bilit y a n d Destr ucti o n of S p o ns or -S u p plie d Trial Vacci ne  ..........................5 1  
9. 0  
T RI A L P L A N  ....................................................................................................................5 3  
9. 1  
Trial Pr oce d ur es  ...........................................................................................................5 3  
9. 1. 1  I nf or me d C o nse nt a n d Pe diatric Asse nt F or m .......................................................5 3  
9. 1. 2  De m o gra p hics, M e dical Hist or y a n d Pri or M e dicati o ns  ........................................5 3  
9. 1. 3  D oc u me ntati o n of Trial E ntra nce/ Ra n d o mizati o n  .................................................5 4  
9. 1. 4  P h ysical E x a mi nati o n .............................................................................................5 5  
9. 1. 5  Vital Si g ns  ..............................................................................................................5 5  
9. 1. 6  I m m u n o ge nicit y Assess me nts ................................................................................5 5  
9. 1. 7  Pr ocessi n g, La beli n g a n d St ora ge of Bi ol o gical Sa m ples  .....................................5 6  
9. 1. 8  Safet y Assess me nts  ................................................................................................5 6  
9. 1. 9  C o ntrace pti o n a n d Pre g n a nc y A v oi da n ce Pr oce d ure  .............................................5 6  
9. 1. 1 0  Pre g n a nc y  ...............................................................................................................5 6  
9. 1. 1 1  D oc u me ntati o n of S u bjects W h o Are N ot Ra n d o mize d  ........................................5 7  
9. 2  
M o nit ori n g S u bject C o m plia nce  ..................................................................................5 7  
9. 3  
Sc he d ule of O bser vati o ns a n d Pr oce d ures  ...................................................................5 7  
9. 3. 1  Pre -Vacci nati o n Pr oce d ures ( Da y 1 [ M 0], Da y 9 0 [ M 3] a n d Da y 1 8 0 [ M 6])  .......5 7  
9. 3. 2  Vacci n ati o n Pr oce d ures ( Da y 1 [ M 0], Da y 9 0 [ M 3] a n d Da y 1 8 0 [ M 6])  .............5 8  
9. 3. 3  P ost -Vacci nati o n Pr oce d ures ( Da y 1 [ M 0], Da y 9 0 [ M 3] a n d Da y 1 8 0 [ M 6])  .....5 8  
9. 3. 4  Site Visits after Vacci nati o n ( Da y 3 0 [ M 1], Da y 1 2 0 [ M 4] a n d Da y 2 1 0 [ M 7])  ..6 1  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 1 3  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
9. 3. 5  P h o ne C o ntacts - Re mi n der Calls  ..........................................................................6 1  
9. 3. 6  P h o ne C o ntacts –  Safet y Call  .................................................................................6 2  
9. 3. 7  Fi nal ( E n d of Trial) Visit ( Da y 3 6 0 [ M 1 2])  ...........................................................6 2  
9. 3. 8  P ost -Trial Care  .......................................................................................................6 2  
9. 4  
Bi ol o gic al Sa m ple Rete nti o n a n d Destr ucti o n  .............................................................6 2  
1 0. 0  
A D V E R S E E V E N T S  .........................................................................................................6 3  
1 0. 1  
Defi niti o ns ....................................................................................................................6 3  
1 0. 1. 1  A d verse E v e nts  ......................................................................................................6 3  
1 0. 1. 2  S olic ite d A d verse E ve nts .......................................................................................6 3  
1 0. 1. 3  A d verse E v e nts of S peci al I nt erest  ........................................................................6 4  
1 0. 1. 4  Me dicall y -Atte n de d A d verse E ve nts  .....................................................................6 4  
1 0. 1. 5  Seri o us A d verse E v e nts  .........................................................................................6 5  
1 0. 2  
Ca usalit y of A Es  ..........................................................................................................6 5  
1 0. 2. 1  Relati o ns hi p t o Trial Pr oce d ures  ............................................................................6 5  
1 0. 2. 2  O utc o me of A d v erse E v e nts  ..................................................................................6 6  
1 0. 3  
A d diti o nal P oi nts t o C o nsi der f or A d verse E v e nts  ......................................................6 6  
1 0. 4  
Pr oce d ures  ....................................................................................................................6 7  
1 0. 4. 1  C ollecti o n a n d Re p orti n g of A d verse E ve nts .........................................................6 7  
1 0. 4. 2  C ollecti o n a n d Re p orti n g of S olicite d A Es  ............................................................6 8  
1 0. 4. 3  C ollecti o n a n d Re p orti n g of A d verse E ve nts of S p ecial 
I nterest/ Me dicall y-Atte n de d A d verse E ve nts  ........................................................6 8  
1 0. 4. 4  C ollecti o n a n d Re p orti n g of Seri o us A d verse E ve nts ............................................6 8  
1 0. 5  
F oll o w -u p Pr oce d ures  ..................................................................................................6 9  
1 0. 5. 1  A d verse E v e nts  ......................................................................................................6 9  
1 0. 5. 2  Seri o us A d verse E v e nts  .........................................................................................6 9  
1 0. 5 . 3 Safet y R e p orti n g t o I n vesti gat ors, I n v esti gati o nal Re vie w B o ar ds or 
I n d e pe n de nt Et hics C o m mittees, a n d Re g ul at or y A ut h orities ...............................6 9  
1 0. 5. 4  P ost -Trial E ve nts  ....................................................................................................7 0  
1 1. 0  
T RI A L -S P E CI FI C R E Q UI R E M E N T( S)  ...........................................................................7 1  
1 1. 1  
Trial -S pecific C o m mittees  ...........................................................................................7 1  
1 1 . 1. 1 Data M o nit ori n g C o m mittee  ..................................................................................7 1  
1 2. 0  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  .............................................................7 2  
1 2. 1  
Case Re p ort F or ms ( Electr o nic) ...................................................................................7 2  
1 2. 2  
Rec or d Rete nti o n  .........................................................................................................7 2  
1 3. 0  
S T A TI S TI C A L M E T H O D S  ..............................................................................................7 4  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 1 4  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
1 3. 1  
Sta tistical a n d A nal ytical Pla ns ....................................................................................7 4  
1 3. 1. 1  A nal ysis Sets  ..........................................................................................................7 4  
1 3. 1. 2  A nal ysis of De m o gra p hi cs a n d Ot her Baseli ne C haract eristics  ............................7 4  
1 3. 1. 3  I m m u n o ge nicit y A n al ysis ......................................................................................7 4  
1 3. 1. 4  Safet y A nal ysis  ......................................................................................................7 5  
1 3. 2  
I nteri m A nal ysis a n d Criteria f or Earl y T er mi nati o n ...................................................7 6  
1 3. 3  
Deter mi nati o n of Sa m ple Size  .....................................................................................7 6  
1 4. 0  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  .................................................7 7  
1 4. 1  
Trial -Site M o nit ori n g Visits  .........................................................................................7 7  
1 4. 2  
Pr ot oc ol De viati o ns  ......................................................................................................7 7  
1 4. 3  
Q ua lit y Ass ura nce A u dits a n d Re g ul at or y A ge n c y I ns p ecti o ns ..................................7 7  
1 4. 4  
Trial Ris k Ma na ge me nt ................................................................................................7 8  
1 5. 0  
E T HI C A L A S P E C T S O F T H E T RI A L  .............................................................................7 9  
1 5. 1  
I nstit uti o nal Re vie w B oar d a n d/ or I n de pe n de nt Et hics C o m mittee A p pr o val ............7 9  
1 5. 2  
S u bject I nf or mati o n, I nf or me d C o nse nt/ Pe diatric Asse nt, a n d S u bject 
A ut h oriz ati o n  ...............................................................................................................8 0  
1 5. 3  
S u bject C o nfi de ntialit y  ................................................................................................8 1  
1 5. 4  
Cli nical Trial Re gistrati o n, P u blicati o n a n d Discl os ure P olic y  ...................................8 1  
1 5. 4. 1  Cli nical Trial Re gistrati o n ......................................................................................8 1  
1 5. 4. 2  Cli nical Trial Res ults Discl os ure  ...........................................................................8 1  
1 5. 4. 3  P u blicati o n of Trial Res ults  ...................................................................................8 2  
1 5. 5  
I ns ura nce a n d C o m pe nsati o n f or I nj ur y .......................................................................8 2  
1 6. 0  
R E F E R E N C E S  ..................................................................................................................8 3  
 
LI S T O F I N -T E X T T A B L E S  
Ta ble 2.a  
Sc he d ule of Trial Pr oce d ures ( Visits 1 t o 7 [ Da y 1 ( M 0) t o Da y 3 6 0 ( M 1 2)])  .....2 5  
Ta ble  8.a  
S p o ns or -S u p plie d Trial Vacci n es  ..........................................................................4 9  
Ta ble  1 0.a  
S olicite d L ocal (I njecti o n Site) Reacti o ns a n d S yst e mic A d verse E ve nts  .............6 3  
Ta ble  1 0. b  
Se verit y Scales f or S olicite d Para meters  ...............................................................6 4  
 
LI S T O F I N -T E X T FI G U R E S  
Fi g ure 2. a  
Sc he matic of Trial D esi g n D E N -3 0 8  .....................................................................1 8  
Fi g ure  6. a  
Sc he matic of Trial D esi g n D E N -3 0 8  .....................................................................3 7  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 1 5  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
LI S T O F A P P E N DI C E S  
A p pe n di x  A  
Res p o nsi bilities of t he I n vesti gat or  ........................................................................8 5  
A p pe n di x  B  
I n v esti gat or C o nse nt t o Use of Pers o nal I nf or mati o n ............................................8 7  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 1 6  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
2. 0  
T RI A L S U M M A R Y  
N a me of S p o ns or:  
T a ke d a Vacci nes, I nc.  
4 0 La n ds d o w ne Street,  
Ca m bri d ge, M A 0 2 1 3 9,  
U S A  
Pr o d uct N a me:  
De n g ue T etra vale nt Vacci ne 
( Li ve, Atte n uate d) ( T D V) 
Tri al Title:  A P hase 3, O pe n -La b el, Ra n d o mize d Trial t o I n vesti gate t he I m m u n o ge nicit y a n d Safet y of t he 
C o -a d mi nistrati o n of a S u bc ut a ne o us De n g ue T etra vale nt V acci ne ( Li ve Atte n uate d) ( T D V) a n d a n I ntra m usc ular 
Rec o m bi na nt 9 -Vale nt H u ma n P a pill o ma vir us ( 9 v H P V ) Vacci ne i n S u bj ects A ge d ≥9 t o < 1 5 Years i n a n E n de mic 
C o u ntr y f or De n g ue  
I N D N o.: N ot a p plica ble  
E u dr a C T N o.: N ot a p plica ble  
Tri al I de ntifier:  D E N -3 0 8  
P h ase:  3  
Bli n di n g Sc he m a:  O pe n -la bel 
I n dic ati o n: Pre ve nti o n of de n g ue fe ver of a n y se verit y d ue t o a n y ser ot y pe  
B ac k gr o u n d:  
De n g ue fe ver is ca use d b y i nfecti o n wit h t he wil d t y pe de n g ue vir us ( D E N V), a ri b o n uclei c aci d vir us t hat occ urs as 
4  rec o g nize d ser ot y pes, D E N V-1, D E N V -2, D E N V -3, or D E N V -4. T hese de n g ue vir uses are tra ns mitte d t o h u ma ns 
b y m os q uit oes ( pri maril y Ae d es ae g y pti). T he 4 de n g ue vir uses are e n de mic i n Asia, Ce ntr al a n d S o ut h A merica, t he 
Cari b bea n, t he P acific Isla n ds, a n d parts of Africa. T here are a n esti mate d 3 9 0 milli o n de n g ue i nfecti o ns per year 
w orl d wi de, w hic h is m ore t ha n 3 ti mes t he pre vi o us W orl d Heal t h Or ga nizati o n ( W H O) esti mate of 5 0 t o 1 0 0 milli o n 
cases. E ver y year, ar o u n d 5 0 0, 0 0 0 cases of de n g ue he m orr ha gic fe ver ( D H F) re q uire h os pit alizati o n wit h a n esti mate d 
deat h rate of 2. 5 %, pri maril y i n c hil dre n. It is esti mate d t hat 3. 9 billi o n pe o ple are a t ris k of de n g ue i nfecti o n. 
De n g ue fe ver is cli nicall y defi ne d as a n ac ute fe brile ill ness wit h 2 or m ore of t he f oll o wi n g ma nifestati o ns: hea dac he, 
retr o-or bital p ai n, m yal gia, art hral gia, ras h, he m orr ha gic ma nifestati o ns, or le u k o pe nia, a n d occ urre nce at  t he sa me 
l ocati o n a n d ti me as ot her c o nfir me d cases of de n g ue fe ver. T he m ost se vere f or ms of de n g ue i nfecti o n –  D H F a n d 
de n g ue s h oc k s y n dr o me ( D S S) –  are life t hreate ni n g. Pri mar y i nfecti o n wit h a n y o ne of t he 4 de n g ue ser ot y pes is 
t h o u g ht t o res ult i n life-l o n g pr otecti o n fr o m re-i nfecti o n b y t he sa me ser ot y pe, b ut d oes n ot pr otect a gai nst a 
sec o n dar y i nfecti o n b y o ne of t he ot her 3 de n g ue ser ot y pes, w hic h ma y lea d t o a n i ncrease d ris k of se vere disease 
( D H F/ D S S). 
Treat me nt of de n g ue fe ver is base d s olel y o n me dical ma na ge me nt of si g ns a n d s y m pt o ms, wit h fl ui d re place me nt 
re q uire d f or he m orr ha gic or s h oc k cases. A n a nti viral t hera p y f or de n g ue vir us i nfecti o n is n ot a vaila ble at t his ti me . 
Pre ve nti ve meas ures t hat rel y o n m os q uit o c o ntr ol a n d i n di vi d ual p r otecti o n are of li mite d efficac y, c o m ple x t o 
i m ple me nt a n d q uesti o na ble i n ter ms of c ost-effecti ve ness. T here is a great u n met gl o bal p u blic healt h nee d f or a safe 
a n d effecti ve vacci ne t o re d uc e t he m or bi dit y a n d m ortalit y ass ociate d wit h de n g ue diseas e.  Vacci ne de vel o p me nt has 
f oc use d o n tetra vale nt vacci nes t hat pr o vi de pr otecti o n a gai nst all 4 de n g ue ser ot y pes si m ulta ne o usl y si nce all 
4  de n g ue ser ot y pes c o m m o nl y c o -circ ulate i n e n de mic areas. A first rec o m bi na nt de n g ue vacci ne (c hi meric yell o w 
fe ver vir us-de n g ue vir us tetra v ale nt de n g ue vacci ne [ C Y D -T D V]) has bee n a p pr o ve d si nce 2 0 1 5 i n se veral Asia n a n d 
Lati n A merica n c o u ntries as well as i n t he U nite d States a n d i n t he E ur o pea n U ni o n. Cli nic al data i n dicate a n 
u nfa v ora ble ris k -be nefit pr ofil e f or c hil dre n a ge d < 9 years wit h t his first a p pr o ve d vacci ne.  A d diti o nall y, vacci ne 
efficac y was differe nt b et wee n ser ot y pes a n d de pe n de d o n de n g ue pre -e x p os ure stat us . M ore rece nt a nal yses f o u n d 
t hat pe o ple w h o ha d n ot b ee n i nfecte d b y de n g ue vir us bef ore vacci nati o n ha d a hi g her ris k of getti n g se vere disease 
w he n t he y were i nfecte d wit h de n g ue vir us after vacci nati o n wit h C Y D -T D V . I n a re vise d Strate gic A d vis or y Gr o u p 
of E x perts o n I m m u nizati o n ( S A G E) rec o m me n dati o n i n A pril 2 0 1 8, t he S A G E c o ncl u de d t hat f or c o u n tries 
c o nsi deri n g C Y D -T D V vacci nati o n as part of t heir de n g ue c o ntr ol pr o gra m, a “ pre -vacci nati o n scree ni n g strate g y” 
w o ul d be t he preferre d o pti o n, i n w hic h o nl y de n g ue -ser o p ositi ve pers o ns are vacci nate d. He nce, t here is a c o nti n ue d 
u n met p u blic healt h nee d f or safer a n d m ore efficaci o us de n g ue vacci nes . 
De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d) ( T D V) –  B ac k gr o u n d:  
T he i n vesti gati o nal vacci ne T D V, als o k n o w n as T A K -0 0 3, c o nsists of 1 m olec ularl y c hara cterize d, atte n uate d de n g ue 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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vir us ser ot y pe 2 strai n  de n ote d as t he de n g ue vir us ser ot y pe 2 bac k b o ne a n d 3 rec o m bi na nt de n g ue vir us strai ns 
e x pressi n g s urface a nti ge ns c orres p o n di n g t o D E N V ser ot y p es 1 -4. T he de n g ue vir us ser ot y pe 2 bac k b o ne is base d 
u p o n t he atte n uate d la b orat or y -deri ve d D E N V -2 vir us stra i n, ori gi nall y is olate d at Ma hi d ol U ni versit y, Ba n g k o k, 
T haila n d a n d ge nerate d b y 5 3 serial passa ges i n pri mar y d o g ki d ne y ( P D K) cells ( D E N V -2  P D K -5 3) . T he 
rec o m bi na nt, atte n uate d vacci ne strai ns f or de n g ue ser ot y pes 1, 3 a n d 4 were e n gi neere d b y s u bstit uti n g t he str uct ural 
ge nes, pre -me m bra ne ( pr M) a n d e n vel o pe ( E), of t he de n g ue vir us ser ot y pe 2 bac k b o ne  wit h t he pr M a n d E ge nes of 
t he D E N V vir us strai ns, D E N V-1 1 6 0 0 7, D E N V -3 1 6 5 6 2 or D E N V -4 1 0 3 6 vir us, res pecti vel y. T h us, T D V is 
c o m prise d of 4 de n g ue vir us strai ns: de n g ue vir us ser ot y pe 1 (li ve, atte n uate d), de n g ue vir us ser ot y pe  2 (li ve, 
atte n uate d), de n g ue vir us ser ot y pe 3 (li ve, atte n uate d), a n d de n g ue vir us ser ot y pe  4 (li ve, atte n uate d). All 4 de n g ue 
vir us ser ot y pes are pr o d uce d i n Ver o cells b y rec o m bi na nt d e o x yri b o n ucleic aci d ( D N A) tec h n ol o g y. De n g ue vir us 
ser ot y pes 1, 3, a n d 4 pr o d ucts c o ntai n ge neticall y m o difie d or ga nis ms . S pecificall y, ge nes of ser ot y pe -s pecific s urface 
pr otei ns are e n gi neere d i nt o t he de n g ue vir us ser ot y pe 2 bac k b o ne . 
N o ncli nic al st u dies carrie d o ut i n mice a n d n o n -h u ma n pri mates ha ve de m o nstrate d a satisfact or y safet y, 
i m m u n o ge nicit y, a n d efficac y pr ofile of T D V. A d diti o nall y, data fr o m c o m plete d p hase 1 a n d p hase 2 cli nical trials i n 
h u ma ns ha ve s h o w n satisfact or y react o ge nici t y, safet y a n d i m m u n o ge nicit y pr ofiles of T D V i n healt h y a d ults i n 
n o n -e n de mic areas as well as i n healt h y a d ults a n d c hil dre n i n e n de mic areas i n Asia a n d Lati n A merica. O n g oi n g a n d 
c o m plete d p hase 2 trials ha ve e na ble d t he selecti o n of a fi nal T D V d ose ( l y o p hilize d f or m ulati o n) a n d a 2-d ose 
vacci nati o n re gi me n ( 2 si n gle d oses) a d mi nistere d 3 m o nt hs (ie, 9 0  da ys) a p art b y s u bc uta ne o us ( S C) i nj ecti o n f or use 
i n t he o n g oi n g pi v otal pr o gra m. Res ults fr o m a n i nteri m a nal ysis f or P art  1 of t he p hase 3 trial D E N -3 0 1  s h o we d t hat 
t he pri mar y efficac y e n d p oi nt was met. I n partic ular, t he dat a de m o nstrate d vacci ne effica c y of 2 d oses of T D V i n 
pre ve nti n g vir ol o gicall y -c o nfir me d de n g ue fe ver i n d uce d b y a n y de n g ue ser ot y pe occ urri n g fr o m 3 0 da ys p ost -sec o n d 
vacci nati o n  ( Da y 1 2 0 [ M o nt h 4 ( M 4)]) u ntil t he e n d of P art 1. 
T he c urre nt i n vesti gat or’s br oc h ure pr o vi des a d diti o nal pr o d uct i nf or mati o n a n d a m ore detaile d re vie w of n o ncli nical 
st u dies a n d cli nical trials. 
R ati o n ale  f or t he Pr o p ose d Tri al: 
T he W H O rec o m me n ds t hat ne w vacci nes s h o ul d be i ntr o d uce d acc or di n g t o e xisti n g nati o nal i m m u nizati o n 
pr o gra ms. Rec o m bi na nt 9 -val e nt h u ma n pa pill o ma vir us  ( H P V) vacci ne is rec o m me n de d i n a 2-d ose sc he d ule 6  t o 
1 2  m o nt hs a p art i n s u bj ects 9 t hr o u g h 1 4 years of a ge. F urt her, if t he sec o n d d ose is a d mi nistere d earlier t ha n 5 m o nt hs 
after t he first d ose, t he n a t hir d d ose s h o ul d be a d mi nistere d at least 4 m o nt hs after t he sec o n d d ose.  
Ma n y si milarities e xist bet wee n t he pr o p ose d vacci nati o n sc he d ule f or T D V a n d t he a p pr o ve d sc he d ule f or 
9 -vale nt  H P V ( 9 v H P V ) vacci ne, i ncl u di n g t he o verla p pi n g t ar get a ge gr o u p a n d t he p ote ntial deli ver y t hr o u g h sc h o ol 
i m m u nizati o n pr o gra ms.  
I n or der t o a v oi d barriers t o t he i ncl usi o n of T D V i n r o uti ne nati o nal vacci nati o n pr o gra ms, t he i m pact of T D V o n 
vacci nes a d mi nistere d via s uc h pr o gra ms nee ds t o be e xa mi ne d. T his is partic ularl y rele va nt f or l o w -i nc o me c o u ntries 
w here t he c ost of a sta n d al o ne vacci nati o n c o ul d be t o o hi g h, a n d p ote ntiall y u n der mi ne T D V u pta ke, if i ncl usi o n i n 
r o uti ne vacci ne sc he d ules wer e n ot p ossi ble.  
Wit h t his trial, we ai m t o pr o vi de i m m u n o ge nicit y a n d safet y data o n t he c o -a d mi nistrati o n of 9 v H P V vacci ne wit h 
T D V i n  healt h y s u bj ects a ge d ≥9 t o < 1 5  years at t he ti me of i nf or me d c o nse nt i n or der t o facilitate i ncl usi o n i nt o 
esta blis he d vacci nati o n sc he d ules a n d miti gate t he af ore -me nti o ne d pr o ble ms. I n t his trial, a p pr o xi matel y 6 1 4 s u bj ects 
are pla n ne d t o be e nr olle d.  
T he trial will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol, I nter nati o nal C o u ncil f or Har m o nisati o n of T ec h nical 
Re q uire me nts f or P har mace uti cals f or H u ma n Use ( I C H) a n d g o o d cli nical practice ( G C P) g ui deli nes, a n d a p plica ble 
re g ulat or y re q uire me nts. 
Tri al Desi g n:  
T his is a p hase 3, o pe n -la bel, ra n d o mize d, m ultice nter trial i n 6 1 4 healt h y s u bj ects a ge d ≥9 t o < 1 5  years i n e n de mic 
areas f or de n g ue, t o i n vesti gat e t he i m m u n o ge nicit y a n d safet y of t he c o -a d mi nistrati o n of T D V a n d 9 v H P V  vacci ne 
vs 9 v H P V  vacci n e al o ne. S u bj ects will be ra n d o mize d e q uall y t o 1 of 2 gr o u ps ( 3 0 7 s u bj ects per trial gr o u p):  
•  Gr o u p 1: first d oses of 9 v H P V vacci ne + T D V c o -a d mi nistere d o n Da y 1 ( M o nt h 0 [ M 0]), sec o n d d ose of T D V 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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a d mi nistere d o n Da y 9 0 ( M 3), sec o n d d ose of 9 v H P V vacci ne a d mi nistere d o n Da y 1 8 0 ( M 6).  
•  Gr o u p 2: first d ose of 9 v H P V vacci ne a d mi nistere d o n Da y 1 ( M 0), sec o n d d ose of 9 v H P V vacci ne a d mi nistere d 
o n Da y 1 8 0 ( M 6).  
C o nc o mita ntl y a d mi nistere d vacci nes will be i nj ecte d i nt o o p p osite ar ms. All s u bj ects will be f oll o we d -u p f or 
6  m o nt hs after t he last trial va cci nati o n, s o t he trial d urati o n will be a p pr o xi matel y 3 6 0 da ys ( or 1 2 m o nt hs) f or eac h 
s u bj ect. 
T he sc he matic of t he trial desi g n a n d bl o o d dra w sc he d ule is i ncl u de d as Fi g ure 2 .a. 
Fi g ure 2 .a  
Sc he m atic of Tri al Desi g n D E N -3 0 8  
 
I m m u n o ge nicit y e val uati o n 
Bl o o d sa m ples f or t he meas ur e me nt of H P V t otal i m m u n o gl o b uli n G ( Merc k assa y) f or b ot h Gr o u ps 1 a n d 2 will be 
c ollecte d at pre -first vacci nati o n ( Da y 1 [ M 0]) a n d at 1 m o nt h p ost-sec o n d 9 v H P V vacci nati o n ( Da y 2 1 0 [ M 7]). 
Bl o o d sa m ples f or t he meas ure me nt of de n g ue ne utralizi n g a nti b o dies ( b y micr o ne utralizati o n test 5 0 % [ M N T 5 0]) will 
be c ollecte d f or Gr o u p 1 o nl y at pre -first vacci nati o n ( Da y 1 [ M 0]) a n d at 1 m o nt h p ost-se c o n d T D V vacci nati o n 
( Da y 1 2 0 [ M 4]).  
Safet y e val uati o n  
•  Diar y car ds will be distri b ute d t o all s u bj ects’ le gall y a ut h orize d re prese ntati ves ( L A Rs) f or t he rec or di n g of: 
− S olicite d l ocal (i nj ecti o n site) reacti o ns f or 7 da ys f oll o wi n g vacci nati o n ( da y of vacci nati o n + 6 da ys) o n Da y 1 
( M 0) a n d Da y 9 0 ( M 3). C ollecti o n starti n g o n Da y 1 ( M 0) will b e f or b ot h i nj ecti o n sites a n d f or s u bj ects i n 
Gr o u ps 1 a n d 2, a n d c oll ecti o n starti n g o n Da y 9 0 ( M 3) will o nl y be f or s u bj ects i n Gr o u p 1 after t he sec o n d 
T D V d ose.  
Reacti o ns will i ncl u de: i nj ecti o n site pai n, i nj ecti o n site er yt he ma a n d i nj ecti o n site s welli n g.  
− S olicite d s yste mic a d verse e ve nts ( A Es) f or 1 4 da ys f oll o wi n g vacci nati o n ( da y of vacci nati o n + 1 3 da ys) o n 
Da y 1 ( M 0) a n d Da y 9 0 ( M 3). C ollecti o n starti n g o n Da y 1 ( M 0) will be f or b ot h i nj ecti o n sites a n d f or s u bj ects 
i n Gr o u ps 1 a n d 2, a n d c ollecti o n starti n g o n Da y 9 0 ( M 3) will o nl y be f or s u bj ects i n Gr o u p 1 after t he sec o n d 
T D V d ose.  
E ve nts will i ncl u de:  (fe ver defi ne d as b o d y te m perat ure ≥3 8. 0° C [ ≥1 0 0. 4° F]), ast he nia, malaise, hea dac he a n d 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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m yal gia.  
•  U ns olicite d A Es f or 2 8 da ys f oll o wi n g vacci nati o n ( da y  of vacci nati o n + 2 7 da ys) o n Da y 1 ( M 0) ( Gr o u p 1 a n d 2) 
a n d Da y 9 0 ( M 3) ( Gr o u p 1). 
•  S A Es will be rec or de d f or t he trial d urati o n ( Gr o u p 1 a n d 2).  
Data will be c ollecte d usi n g a n electr o nic Case Re p ort F or m (e C R F).  
Pri m ar y O bjecti ve:  
T o de m o nstrate t he n o n -inferi orit y ( NI) of t he i m m u ne res p o nse (i n ter ms of ge o metric mea n titers [ G M Ts]) t o 2  d oses 
of 9 v H P V vacci ne, 1 c o -a d mi nistere d wit h T D V, c o m pare d wit h 2 d oses of 9 v H P V vacci ne a d mi nistere d al o ne.  
Sec o n d ar y O bjecti ves:  
I m m u n o ge nicity 
•  
T o descri be t he i m m u ne res p o nse t o H P V (i n ter ms of ser ores p o nse) i n s u bj ects a d mi nister e d 2 d oses of 9 v H P V 
vacci ne, 1 c o -a d mi nistere d wit h T D V, c o m pare d wit h s u bj ects a d mi nistere d 2 d oses of 9 v H P V vacci ne al o ne.  
•  
T o descri be t he i m m u ne res p o nse t o T D V at 1 m o nt h f oll o wi n g a sec o n d d ose of T D V gi ve n 3 m o nt hs after t he 
first d ose of T D V a d mi nistere d c o nc o mita ntl y wit h 9 v H P V vacci ne. 
S afety  
•  
T o descri be t he safet y pr ofile after a d mi nistrati o n of T D V c o nc o mita ntl y wit h 9 v H P V vac ci ne . 
S u bject P o p ul ati o n:  
He alt h y S u bjects:  Yes  
A ge R a n ge:  ≥9 t o < 1 5  years at t he ti me of i nf or me d c o nse nt (ie, fr o m 9 years of a ge t hr o u g h t o 1 4 years a n d 3 6 4 da ys 
of a ge bef ore trial e nr oll me nt)  
Pl a n ne d N u m ber of S u bjects:  6 1 4  
Pl a n ne d N u m ber of Tri al Ar ms:  2 gr o u ps i n a 1: 1 rati o  ( 3 0 7 s u bj ects i n eac h trial gr o u p). 
I ncl usi o n Criteri a:  
1.  T he s u bj ect is a ge d ≥9 t o < 1 5  years.  
2.  Male or fe male.  
3.  S u bj ects w h o are i n g o o d healt h at t he ti me of e ntr y i nt o t he trial as deter mi ne d b y me dical hist or y, p h ysical 
e xa mi nati o n (i ncl u di n g vital si g n s), a n d t he cli nical j u d g me nt of t he i n vesti gat or. 
4.  T he s u bj ect has si g ne d a n d dat e d a n asse nt f or m a n d/ or pare nt(s) or L A R(s)  ha ve si g ne d a n d date d a writte n 
i nf or me d c o nse nt f or m, i ncl u di n g a n y re q uire d pri vac y a ut h orizati o n f or m, pri or t o t he i niti ati o n of a n y trial 
pr oce d ures, after t he nat ure of t he trial has bee n e x plai ne d ac c or di n g t o l ocal re g ulat or y re q uire me nts.  
5.  S u bj ects w h o ca n c o m pl y wit h trial pr oce d ures a n d are a vaila ble f or t he d urati o n of f oll o w -u p.  
E xcl usi o n Criteri a:  
1.  S u bj ects wit h a n ele va te d oral te m perat ure ≥3 8° C ( ≥1 0 0. 4° F) wit hi n 3 da ys of t he i nte n de d date of vacci nati o n 
(c o nsi der w het her a p plica ble as a n e xcl usi o n criteri o n or criteri o n f or dela y, see bel o w).  
2.  S u bj ects wit h c o ntrai n dicati o ns, war ni n gs a n d/ or preca uti o ns t o vacci nati o n w it h 9 v H P V vacci ne as s pecifie d 
wit hi n t he prescri bi n g i nf or mati o n.  
3.  K n o w n h y perse nsiti vit y or all er g y t o a n y of t he trial vacci ne c o m p o ne nts (i ncl u di n g e xci pie nts of t he trial 
vacci nes).  
4.  S u bj ects wit h be ha vi oral or c o g niti ve i m pair me nt or ps yc hiatric disease t hat, i n t he o pi ni o n of t he i n vesti gat or, 
ma y i nterfere wit h t he s u bj ect’s a bilit y t o partici pate i n t he trial.  
5.  S u bj ects  wit h a n y hist or y of pr o gressi ve or se vere ne ur ol o gi c dis or der, seiz ure dis or der or ne ur o -i nfla m mat or y 
disease (e g, G uillai n -B ar ré s y n dr o me). 
6.  S u bj ects wit h a hist or y of or a n y c urre nt ill ness t hat, i n t he o pi ni o n of t he i n vesti gat or, mi g ht i nterfere wit h t he 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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res ults of t he trial or p ose a d diti o nal ris k t o t he s u bj ects d ue t o partici pati o n i n t he trial. 
7.  K n o w n or s us pecte d i m pair me nt /alterati o n of i m m u ne f u ncti o n, i ncl u di n g: 
a. 
C hr o nic use of oral ster oi ds (e q ui vale nt t o 2 0 m g/ da y pre d nis o ne ≥1 2 wee ks/ ≥2 m g/ k g b o d y wei g ht/ da y 
pre d nis o ne ≥2 wee ks) wit hi n 6 0 da ys pri or t o Da y 1 ( M 0) ( use of i n hale d, i ntra nasal, or t o pical 
c ortic oster oi ds i s all o we d). 
b.  Recei pt of pare nteral ster oi ds (e q ui vale nt t o 2 0 m g/ da y pre d nis o ne ≥1 2 wee ks/ ≥2 m g/ k g b o d y wei g ht/ da y 
pre d nis o ne ≥2 wee ks) wit hi n 6 0 da ys pri or t o Da y 1 ( M 0).  
c. 
A d mi nistrati o n of i m m u n o gl o b uli ns a n d/ or a n y bl o o d pr o d ucts wit hi n t he 3 m o nt hs pri or  t o Da y 1 ( M 0) or 
pla n ne d a d mi nistrati o n d uri n g t he trial.  
d.  Recei pt of i m m u n osti m ula nts wit hi n 6 0 da ys pri or t o Da y 1 ( M 0).  
e. 
I m m u n os u p pressi ve t hera p y s uc h as a nti-ca ncer c he m ot hera p y or ra diati o n t hera p y wit hi n 6 m o nt hs pri or t o 
Da y 1 ( M 0).  
f. 
H u ma n i m m u n o defi cie nc y vir us ( HI V) i nfecti o n or HI V -relate d disease. 
g.  He p atitis B vir us i nfecti o n.  
h.  He p atitis C vir us i nfecti o n.  
i. 
Ge netic i m m u n o deficie nc y.  
8.  A b n or malities of s ple nic or t h y mi c f u ncti o n.  
9.  S u bj ects  wit h a k n o w n blee di n g diat hesis, or a n y c o n diti o n t hat ma y be ass ociate d wit h a pr ol o n ge d blee di n g 
ti me. 
1 0.  S u bj ects  wit h a n y seri o us c hr o nic or pr o gressi ve disease acc or di n g t o t he j u d g me nt of t he i n vesti gat or (e g, 
ne o plas m, he mat ol o gic mali g na ncies, i ns uli n de pe n de nt dia betes, car diac, re nal or he patic disease). 
1 1.  S u bj ects  partici pati n g i n a n y cli nical trial wit h a n ot her trial vacci ne 3 0 da ys pri or t o Da y  1 ( M 0) or i nte n di n g t o 
partici pate i n a n ot her cli nical trial at a n y ti me d uri n g t he c o n d uct of t his trial.  
1 2.  S u bj ects w h o recei ve d a n y ot her vacci nes wit hi n 1 4 da ys (f or i na cti vate d vacci nes) or 2 8 da ys (f or li ve vacci nes) 
pri or t o e nr oll me nt i n t his trial or w h o are pla n ni n g t o recei ve a n y vacci ne wit hi n 2 8 da ys of trial vacci ne 
a d mi nistrati o n.  
1 3.  S u bj ects w h o ha ve use d a nti p yretics a n d/ or a nal gesic me dic ati o ns wit hi n 2 4 h o urs pri or t o vacci nati o n. T he 
reas o n f or t heir use ( pr o p h yla xis vers us treat me nt) m ust be d oc u me nte d. Trial e ntr y s h o ul d be dela ye d t o all o w f or 
a f ull 2 4 h o urs t o ha ve passe d si nce last use of a nti p yretics a n d/ or a nal gesic me dicati o ns.  
1 4.  S u bj ects i n v ol ve d i n t h e trial c o n d uct or t heir first -de gree relati ves.  
1 5.  S u bj ects wit h a hist or y of s u bsta nce or alc o h ol a b use wit hi n t he past 2 years.  
1 6.  S u bj ects w h o are pre g na nt or breastfee di n g.  
1 7.  Fe males of c hil d beari n g p ote ntial 1  w h o are se x uall y acti ve a n d w h o ha ve n ot use d a n y of t he acce pta ble 
c o ntrace pti ve met h o ds 2 f or at least 2 m o nt hs pri or t o Da y 1 ( M 0). 
1 8.  Fe males of c hil d beari n g p ote ntial w h o are se x uall y acti ve  a n d w h o ref use t o use a n acce pta ble c o ntrace pti ve 
met h o d u p t o 6 wee ks p ost -fi nal vacci nati o n o n Da y 1 8 0 ( M 6). I n a d diti o n, t he y m ust be a d vise d n ot t o d o nate o va 
d uri n g t his peri o d.  
1 9.  A n y p ositi ve or i n deter mi nate pre g na nc y test.  
                                                 
1  Defi ne d as stat us p ost o nset of me narc he a n d n ot meeti n g a n y of t he f oll o wi n g c o n diti o ns: bilateral t u bal li gati o n (at 
least 1 year pre vi o usl y), bilateral o o p h orect o m y (at least 1 year pre vi o usl y) or h ysterect o m y. 
2 O ne or m ore of t he f oll o wi n g: h or m o nal c o ntrace pti ve (s uc h as oral, i nj ecti o n, tra ns der mal patc h, i m pla nt, cer vical 
ri n g), i ntra uteri ne de vice, m o n o ga m o us relati o ns hi p wit h vas ect o mize d part ner ( part ner m ust ha ve bee n vasect o mize d 
f or at least 6 m o nt hs pri or t o Da y 1 [ M 0]). Ot her c o ntrace pti ve met h o ds ma y be c o nsi dere d i n a gree me nt wit h t he 
S p o ns or a n d will be a p pr o ve d b y t he a p pr o priate et hics c o m mittee.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 2 1  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
2 0.  Pre vi o us a n d pla n ne d vacci nati o n ( d uri n g t he trial c o n d uct), a gai nst a n y fla vi vir us (e xce pt J a pa nese e nce p halitis 
[J E]) i ncl u di n g de n g ue, yell o w fe ver ( Y F) vir uses or tic k-b or ne e nce p halitis.  
2 1.  Pre vi o us a n d pla n ne d vacci nati o n ( d uri n g t he trial c o n d uct) a gai nst H P V.  
2 2.  Pre vi o us par tici pati o n i n a n y cli nical trial of a de n g ue or ot her fla vi vir us (e g, W est Nile [ W N] vir us) ca n di date 
vacci ne, e xce pt f or s u bj ects w h o recei ve d place b o i n t h ose trials.  
2 3.  S u bj ects wit h a c urre nt or pre vi o us i nfecti o n wit h a fla vi vir us s uc h as Zi ka, Y F, J E, W N fe ver, tic k -b or ne 
e nce p halitis or M urra y Valle y e nce p halitis.  
T here ma y be i nsta nces w he n s u bj ects meet all e ntr y criteria e xce pt o ne t hat relates t o tra nsie nt cli nical circ u msta nces 
(e. g., b o d y te m perat ure ele vati o n or rece nt use of e xcl u de d me dicati o n[s] or vacci ne[s]). U n der t hese circ u msta nces, 
eli gi bilit y f or trial e nr oll me nt ma y be c o nsi dere d if t he a p pr o priate wi n d o w f or dela y has passe d, i ncl usi o n/e xcl usi o n 
criteria ha ve bee n rec hec ke d, a n d if t he s u bj ect is c o nfir me d t o be eli gi ble.  
Criteria f or dela y of sec o n d trial vacci ne a d mi nistrati o n at D a y 9 0 ( M 3) or Da y 1 8 0 ( M 6):  
After e nr oll me nt, s u bj ects ma y e nc o u nter cli nical circ u msta nces t hat warra nt a dela y i n t he a d mi nistrati o n of trial 
vacci ne. T hese sit uati o ns are liste d bel o w. I n t he e ve nt t hat a  s u bj ect meets a criteri o n f or dela y of trial vacci ne 
a d mi nistrati o n, t he s u bj ect ma y recei ve t he trial vacci ne(s) o nce t he wi n d o w f or dela y has passe d as l o n g as t he s u bj ect 
is ot her wise eli gi ble f or trial partici pati o n. 
If a n y of t he criteria bel o w occ ur at t he ti me sc he d ule d f or t he trial vacci ne a d mi nistrati o n at Da y 9 0 ( M 3) or Da y  1 8 0 
( M 6), t he s u bse q ue nt d ose ma y be a d mi nistere d at a later date as l o n g as t he s u bj ect is ot her wise eli gi ble t o c o nti n ue 
trial partici pati o n. I n certai n sit uati o ns, t he peri o d of dela y ma y lea d t o de viati o n fr o m t he ti me wi n d o w f or t he 
s u bse q ue nt d ose. T he decisi o n t o vacci nate i n t h ose sit uati o ns will be ma de b y t he i n vesti gat or.  
T he f oll o wi n g cli nical circ u msta nces warra nt a dela y i n t he a d mi nistrati o n of trial vacci ne at  Da y 9 0 ( M 3) or Da y 1 8 0 
( M 6):  
1.  S u bj ects wit h a cli nicall y si g nifica nt acti ve i nfecti o n (as assesse d b y t he i n vesti gat or) or b o d y te m perat ure 
≥3 8. 0° C ( ≥1 0 0. 4° F) wit hi n 3 da ys of pla n ne d trial vacci ne a d mi nistrati o n (c o nsi der at Da y 1 [ M 0] w het her 
a p plica ble  as a n e xcl usi o n crit eri o n, see a b o ve).  
2.  S u bj ects w h o recei ve d a n y ot her vacci nes wit hi n 1 4 da ys (f or i nacti vate d vacci nes) or 2 8 da ys (f or li ve vacci nes) 
pri or t o pla n ne d trial vacci nati o n or bl o o d sa m pli n g.  
3.  K n o w n or s us pecte d altere d or i m paire d i m m u ne f u ncti o n as s pecifie d u n der t he e xcl usi o n criteria.  
4.  S u bj ects w h o ha ve use d a nti p yretics a n d/ or a nal gesic me dic ati o ns wit hi n 2 4 h o urs pri or t o trial vacci nati o n. T he 
reas o n f or t heir use ( pr o p h yla xis vers us treat me nt) m ust be d oc u me nte d. Trial vacci ne a d mi nistrati o n s h o ul d be 
dela ye d t o all o w f or a f ull 2 4 h o urs t o ha ve passe d bet wee n ha vi n g use d a nti p yretics a n d/ or a nal gesic me dicati o ns 
a n d trial vacci ne a d mi nistrati o n.  
C o ntrai n dicati o ns t o trial vacci ne a d mi nistrati o n at Da y 9 0 ( M 3) or Da y 1 8 0 ( M 6):  
T here ar e als o circ u msta nces u n der w hic h recei pt of t he trial vacci nati o n at  Da y 9 0 ( M 3) or Da y 1 8 0 ( M 6) is 
c o ntrai n dicate d i n t his trial. T hese circ u msta nces i ncl u de b ut are n ot li mite d t o a na p h yla xis or se vere h y perse nsiti vit y 
reacti o ns f oll o wi n g t he a d mi nistrati o n of a n earlier trial vacci nati o n at Da y 1 ( M 0) or Da y 9 0 ( M 3), res pecti vel y. If 
t hese reacti o ns occ ur, t he s u bj ect m ust n ot recei ve t he trial vacci nati o n at Da y 9 0 ( M 3) or Da y 1 8 0 ( M 6), res pecti vel y, 
b ut will be e nc o ura ge d t o c o nti n ue trial p artici pati o n f or safet y f oll o w -u p.  
Tri al V acci nes:  
I nvesti g ati o n al v acci ne 
T he i n vesti gati o nal vacci ne, T D V, is a De n g ue T etra vale nt Vacci ne ( Li ve, Atte n uate d)  c o m prise d of a m olec ularl y 
c haracterize d, atte n uate d de n g ue ser ot y pe 2 strai n ( T D V-2), a de n g ue ser ot y pes 2/ 1 rec o m bi na nt strai n ( T D V -1), a 
de n g ue ser ot y pes 2/ 3 rec o m bi na nt strai n ( T D V -3), a n d a de n g ue ser ot y pes 2/ 4 rec o m bi na nt strai n ( T D V -4)  wit h 
p ote ncies of n ot less t ha n 3. 3, 2. 7, 4. 0 a n d 4. 5 l o g 1 0 pla q ue f or mi n g u nits per d ose of T D V -1, T D V -2, T D V -3, a n d 
T D V -4, res pecti vel y. T D V is a l y o p hilize d vacci ne t hat will be rec o nstit ute d i n dil ue nt ( 3 7 m M Na Cl s ol uti o n) pri or t o 
a d mi nistrati o n.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 2 2  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
9v H P V v a cci ne  
T he 9 v H P V vacci ne ( Merc k) is a rec o m bi na nt 9 -vale nt vacci ne c o ntai ni n g t he L 1 pr otei ns f or H P V t y pes 6, 1 1, 1 6, 1 8, 
3 1, 3 3, 4 5, 5 2, a n d 5 8. T he 9 v H P V vacci ne c o ntai ns yeast pr otei n, a n d t he vacci ne a nti ge n is a ds or be d o n a n 
al u mi n u m-c o ntai ni n g a dj u va nt. Eac h d ose of 9 v H P V vacci ne is 0. 5 m L a n d is s u p plie d as a si n gle-d ose vial or i n 
prefille d s yri n ges t hat d o n ot c o ntai n late x.  
R o ute of a d mi nistr ati o n  
T D V will be a d mi nistere d b y t he S C r o ute, 9 v H P V vacci ne will be a d mi nistere d b y t he i ntra m usc ular (I M) r o ute.  
D ur ati o n of t he Tri al a n d S u bject P artici p ati o n:  
T he trial d urati o n f or eac h s u bj ect will be a p pr o xi ma tel y 3 6 0 da ys or 1 2 m o nt hs.  
Criteri a f or E v al u ati o n a n d A n al yses:  
Pri m ar y e n d p oi nt:  
•  
Ge o metric mea n titers ( G M Ts) f or H P V T y pes 6, 1 1, 1 6, 1 8, 3 1, 3 3, 4 5, 5 2, 5 8 o n Da y 2 1 0 ( M 7 ). 
Sec o n d ar y e n d p oi nts:  
I m m u n o ge nicity 
•  
Ser o p ositi vit y rates ( % of s u bj ects ser o p ositi ve) f or H P V T y pes 6, 1 1, 1 6, 1 8, 3 1, 3 3, 4 5, 5 2 a n d 5 8 o n Da y 2 1 0 
( M 7) as meas ure d b y i m m u n o gl o b uli n G bi n di n g assa y (I g G B A) or e q ui vale nt  assa y.  
•  
G M Ts of ne utralizi n g a nti b o dies ( b y M N T 5 0) f or eac h of t he 4 de n g ue ser ot y pes o n Da y 1 2 0 ( M 4). 
•  
Ser o p ositi vit y rates ( % of s u bj ects ser o p ositi ve) f or eac h of t he 4 de n g ue ser ot y pes a n d f or m ulti ple ( 2, 3 or 4) 
de n g ue ser ot y pes o n Da y 1 2 0 ( M 4).  
Defi niti o n of ser o p ositi vit y - De n g ue vir us  
Ser o p ositi vit y is defi ne d as a reci pr ocal ne utralizi n g a nti b o d y titer ≥1 0 f or a n y of t he 4 de n g ue ser ot y pes. 
Defi niti o n of ser o p ositi vit y - H P V  
T he mi ni m u m a nti -H P V titer t hat c o nfers pr otecti ve efficac y has n ot bee n deter mi ne d.  
Ser o p ositi vit y f or H P V is defi ne d as a n a nti -H P V titer greater t ha n or e q ual t o t he pre -s pecifie d ser ostat us c ut -off f or a 
gi ve n H P V t y pe. Ser o ne gati vit y is defi ne d as a n a nti -H P V tit er less t ha n t he pre -s pecifie d s er ostat us c ut-off f or a gi ve n 
H P V t y pe. T he ser ostat us c ut -off is t he a nti b o d y titer le vel a b o ve t he assa y’s l o wer li mit of q ua ntif icati o n t hat relia bl y 
disti n g uis hes sera sa m ples classifie d b y cli nical li keli h o o d of H P V i nfecti o n a n d p ositi ve or ne gati ve stat us b y 
pre vi o us versi o ns of I g G B A or e q ui vale nt assa y .  
Ser u m a nti b o dies t o H P V t y pes 6, 1 1, 1 6, 1 8, 3 1, 3 3, 4 5, 5 2, a n d 5 8 will  be meas ure d wit h a n I g G B A  or e q ui vale nt 
assa y. Titers will be re p orte d i n milli -Merc k u nits/ m L wit h t he use of t he I g G B A.  F or t he l o wer li mits of q ua ntificati o n 
a n d ser ostat us c ut -offs f or eac h of t he 9 vacci ne H P V t y pes , please refer t o t he statistical anal ysis pla n ( S A P) . 
S afety  
•  
Fre q ue nc y a n d se verit y of s olicite d l ocal (i nj ecti o n site) reacti o ns f or 7 da ys ( da y of vacci nati o n + 6 da ys) ( Gr o u p 2 
a n d c ollecte d at eac h i nj ecti o n site i n Gr o u p 1) a n d s olicite d s yste mic A Es f or 1 4 da ys ( da y of vacci nati o n + 1 3 
d a ys) after vacci nati o n o n  Da y  1 ( M 0) ( Gr o u p  1 a n d 2) a n d Da y  9 0 ( M 3) ( Gr o u p  1) . 
•  
P erce nta ge of s u bj ects wit h a n y u ns olicite d A Es f or 2 8 da ys ( da y of vacci nati o n + 2 7 da ys) after vacci nati o n o n 
Da y  1 ( M 0) ( Gr o u p  1 a n d 2) a n d Da y  9 0 ( M 3) ( Gr o u p  1) . 
•  
P erce nta ge o f s u bj ects wit h S A Es t hr o u g h o ut t he trial ( Gr o u p 1 a n d 2).  
St atistic al C o nsi der ati o ns:  
A nal ysis sets  
Safet y set: t he safet y set will c o nsist of all s u bj ects w h o recei ve d at least 1 d ose of T D V or 9 v H P V.  
F ull a nal ysis set ( F A S): t he F A S will i ncl u de all ra n d o mize d s u bj ects w h o recei ve d at least 1 d ose of  trial vacci ne a n d 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 2 3  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
f or w h o m vali d pre-d osi n g ( D a y 0 [ M 0]) a n d at least 1 p ost -d osi n g meas ure me nt ha ve bee n recei ve d f or 
i m m u n o ge nicit y assess me nts. 
P er -pr ot oc ol set ( P P S):  t he P P S will e xcl u de all s u bj ect s ser o p ositi ve f or H P V at B aseli ne a n d will i ncl u de all s u bj ects 
i n t he F A S w h o ha ve n o maj or pr ot oc ol vi olati o ns. T he maj or pr ot oc ol vi olati o n criteria will be defi ne d as part of a 
data re vie w pri or t o t he a nal ysis. T he cate g ories of maj or pr ot oc ol vi olat i o ns i ncl u de: ( 1) n ot meeti n g selecte d e ntr y 
criteria, ( 2) recei vi n g t he wr o n g trial vacci ne, ( 3) recei vi n g pr o hi bite d t hera pies, a n d ( 4) ot her maj or pr ot oc ol 
vi olati o ns t hat ma y be i de ntifi e d d uri n g data re vie ws.  
All s u m maries a n d a nal yses of safet y data will be base d o n t he safet y set. T he pri mar y i m m u n o ge nicit y a nal yses will 
be base d o n t he P P S; a d diti o nal i m m u n o ge nicit y a nal yses ma y be pr o vi de d base d o n t he F A S.  
A nal ysis of de m o gra p hics a n d ot her baseli ne c haracteristics  
A ge, ge n der, race, a n d ot her bas eli ne c haracteristics will be s u m marize d descri pti vel y b y trial gr o u p f or all 
ra n d o mize d s u bj ects.  
 
I m m u n o ge nicit y a nal ysis 
T he pri mar y o bj ecti ve, NI of t he i m m u ne res p o nse t o 2 d oses of 9 v H P V vacci ne w he n c o nc o mita ntl y a d mi nistere d 
wit h T D V c o m pare d t o a d mi nistrati o n of 9 v H P V vacci ne al o ne, will be assesse d i n ter ms of G M Ts o n Da y 2 1 0 ( M 7). 
NI f or eac h H P V t y pe will be c o ncl u de d if t he u p per b o u n d of t he 9 5 % c o nfi de nce i nter val ( CI) f or t he G M T rati o 
( Gr o u p 2/ Gr o u p 1) is less t ha n t he NI mar gi n of 1. 5. O verall NI will be c o ncl u de d if NI re q uire me nt is met f or all 
9  H P V t y pes, t heref ore n o m ulti plicit y a dj ust me nt of first t y p e err or is nee de d a n d 9 5 %  CI will be use d i n eac h 
c o m paris o n.  
Descri pti ve statistics i ncl u di n g 9 5 % CI f or t he pri mar y a n d sec o n dar y e n d p oi nts, i ncl u di n g ser o p ositi vit y rates a n d 
G M Ts, will be c o m p ute d b y trial gr o u p f or all a vaila ble assa ys at all rele va nt ti me p oi nts.  
A n a nal ysis of (c o) varia nce ( A N[ C O] V A) m o del o n t he nat ural l o garit h ms of titer val ues will be use d t o c o m p ute t he 
9 5 % CI of t he G M T rati os, wit h trial gr o u p as a fact or base d o n t he P P S. A si milar, s u p p orti ve A N C O V A, wit h trial 
gr o u p a n d t he nat ural l o garit h ms of pre -vacci nati o n titers as fact ors ma y be pr o vi de d base d o n t he F A S.  
Ha n dli n g of missi n g data will be descri be d  i n t he S A P.  
 
Safet y a nal ysis  
S olicite d A Es  
Prese nce a n d se verit y ( Gra d e) of s olicite d l ocal (i nj ecti o n sit e reacti o ns pai n, i nj ecti o n site er yt he ma a n d i nj ecti o n site 
s welli n g) will be c ollecte d usi n g diar y car ds o n Da y 1 ( M 0) a n d Da y 9 0 ( M 3) f or 7 da ys f oll o wi n g eac h vacci nati o n. I n 
Gr o u p 1, reacti o ns at b ot h i nj ecti o n sites ( T D V a n d 9 v H P V vacci ne) will be c ollecte d o n Da y 1 ( M 0) a n d at t he T D V 
i nj ecti o n site o n Da y 9 0 ( M 3). I n Gr o u p 2, reacti o ns at t he 9 v H P V vacci ne i nj ecti o n site will be c ollecte d o n Da y 1 
( M 0). 
Prese nce a n d se verit y ( Gra d e) of s olicite d s yste mic A Es (fe ver, ast he nia, malaise, hea dac he a n d m yal gia) will be 
c ollecte d usi n g diar y car ds o n Da y 1 ( M 0) a n d Da y 9 0 ( M 3) f or 1 4 da ys f oll o wi n g eac h va cci nati o n. C ollecti o n 
starti n g o n Da y 1 ( M 0) will be f or b ot h i nj ecti o n sites a n d f or s u bj ects i n Gr o u ps 1 a n d 2, a n d c ollecti o n starti n g o n 
Da y 9 0 ( M 3) will o nl y be f or s u bj ects i n Gr o u p 1 after t he s ec o n d T D V d ose.  
F or eac h s olicite d A E, t he n u m ber a n d perce nta ge of s u bj ects wit h l ocal (i nj ecti o n s ite) reacti o ns a n d s yste mic A Es 
will b e s u m marize d b y trial gr o u p a n d e ve nt se verit y f or eac h da y after trial vacci nati o n (i e, Da y 1 t hr o u g h Da y 7 f or 
l ocal [i nj ecti o n site] reacti o ns a n d Da y 1 t hr o u g h Da y 1 4 f or s yste mic A Es), a n d o verall. S u m maries of first o nset of 
eac h e ve nt a n d t he n u m ber of da ys s u bj ects re p orte d e x perie nci n g eac h e ve nt will als o be rec or de d. F or s u bj ects wit h 
m ore t ha n 1 e pis o de of t he sa me e ve nt, t he ma xi m u m se verit y will be use d f or ta b ulati o ns.  
P ersiste nt/ pr ol o n ge d s olicite d l ocal  reacti o ns or s yste mic A Es c o nti n ui n g o n Da y 8 or Da y 1 5, res pecti vel y, f oll o wi n g 
trial vacci nati o n will be assesse d se p aratel y. U nless ot her wise s pecifie d t hese reacti o ns or A Es will n ot be i ncl u de d i n 
t he a nal ys es/ta b ulati o ns of u ns olicite d A Es a n d will ha ve se p arate listi n gs.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 2 4  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
 
U ns olicite d A Es  
U ns olicite d A Es will be assess e d f or 2 8 da ys f oll o wi n g trial vacci nati o n ( da y of vacci nati o n + 2 7 da ys).  
U ns olicite d A Es will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A), a n d s u m marize d 
b y Preferre d T er m ( P T) a n d S yste m Or ga n Class ( S O C) f or eac h trial gr o u p.  
U ns olicite d A Es will be s u m marize d as f oll o ws: b y P T i ncl u di n g e ve nts wit h fre q ue nc y gr eater t ha n a pre -defi ne d 
fre q ue nc y (t he perce nta ge will be s pecifie d i n t he S A P); b y S O C a n d P T; b y S O C, P T, a n d se verit y; a n d b y S O C, P T, 
a n d relati o ns hi p t o t he trial va cci ne(s). S u bj ects re p orti n g m ore t ha n 1 occ urre nce f or t he t er m (le vel) bei n g 
s u m marize d will be c o u nte d o nl y o nce.  
A Es lea di n g t o i n vesti gati o nal vacci ne wit h dra wal or trial dis c o nti n uati o n will be c ollecte d a n d s u m marize d f or t he 
e ntire trial.  
S A Es  
S A Es will be c ollecte d t hr o u g h o ut t he trial. S A Es will be c o de d usi n g Me d D R A, a n d s u m marize d b y P T a n d S O C f or 
eac h trial gr o u p.  
S a m ple Size J ustific ati o n:  
T he sa m ple size calc ulati o n ass u mes a si g nifica nce le vel of 0. 0 2 5 ( o ne -si de d).   
F or t he pri mar y o bj ecti ve of s h o wi n g NI of 9 v H P V G M Ts, t he calc ulati o n ass u mes a NI mar gi n of 1. 5, a tr ue G M T 
rati o of 1 bet wee n trial gr o u ps at Da y 2 1 0 ( M 7), a n d t hat t he nat ural l o garit h ms of t he a nti b o d y titers a gai nst 9 H P V 
t y pes are i n de pe n de nt n or mall y distri b ute d wit h sta n dar d de viati o ns of 0. 9 5, 0. 8 6, 0. 9 8, 0. 9 1, 0. 9 8, 0. 9 4, 1. 0 9, 1. 0 3, 
a n d 0. 9 4. T he lar gest varia bilit y 1. 0 9 was ass u me d a n d use d f or sa m ple size calc ulati o ns f or all 9 s trai ns. 
A sa m ple size of 3 0 7 s u bj ects per gr o u p, wit h a p pr o xi matel y 2 6 1 e val ua ble s u bj ects per trial gr o u p (a dj uste d f or 
a p pr o xi matel y 1 5 % s u bj ects n ot e val ua ble f or t he i m m u n o ge nicit y assess me nts), is s ufficie nt t o ac hie ve 
a p pr o xi matel y 9 0 % p o wer f or s h o wi n g NI f or t he pri mar y o bj ecti ve.  
Sa m ple size calc ulati o ns were perf or me d usi n g n Q uer y A d vis or ® 8.  
I nteri m A n al ysis: 
A n i nteri m a nal ysis of i m m u n o ge nicit y a n d safet y data is pla n ne d w he n all s u bj ects ha ve c o m plete d t he Da y 2 1 0 ( M 7) 
visit. T his will be re p orte d i n a n i nteri m cli nical st u d y re p ort ( C S R). A fi nal C S R will be pre pare d u p o n trial 
c o m pleti o n t o i ncl u de safet y d ata c ollecte d u p t o t he e n d of t he trial o n Da y 3 6 0 ( M 1 2) a n d will als o i ncl u de res ults f or 
t he w h ole trial d urati o n. 
D at a M o nit o ri n g C o m mittee  ( D M C):  
A D M C will ha ve o versi g ht of t his trial. T he D M C f u ncti o ns at a pr o gra m le vel a n d f urt her i nf or mati o n is a vaila ble i n 
t he D M C C harter. 
D E N -3 0 8 Versi o n 5 . 0 (3  M arc h 2 0 2 1)  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 2 5  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
2. 1  
Sc he d ule of Tri al Pr oce d ures  
T a ble 2 .a  
Sc he d ule of Tri al Pr oce d ures ( Visits 1 t o 7 [ D a y 1 ( M 0) t o D a y 3 6 0 ( M 1 2)])  
Visits  
1  
2  
3  
4  
5  
6  
7  
D a y  
D a y 1  
D a y 
3 0  
D a y 9 0  
D a y 
1 2 0  
D a y 1 8 0  
D a y 
2 1 0  
D a y 
3 6 0  
M o nt h  
M 0  
M 1  
M 3  
M 4  
M 6  
M 7  
M 1 2 
( E T) ( a) 
Visit wi n d o w ( d a ys)  
1 ± N A   
3 0  
d a ys  
(-1/ + 7)  
after  
Visit 1  
9 0 d a ys 
(-1 5/ + 2 5) 
after 
Visit 1  
3 0 
d a ys 
(-1/ + 7) 
after 
Visit 3  
9 0 d a ys 
(-1 5/ + 2 5) 
after 
Visit 3  
3 0 
d a ys 
(-1/ + 7) 
after 
Visit 5  
1 8 0 
d a ys 
(-7/ + 1 4) 
after 
Visit 5  
Pr o ce d ures  
 
 
 
 
 
 
 
Si g ne d i nf or me d c o nse nt/ pe di atric asse nt  
X  
 
 
 
 
 
 
Assess me nt of eli gi bilit y criteria  
X  
 
 
 
 
 
 
Re vie w of s yste ms  
X  
 
 
 
 
 
X  
De m o gra p hics, me dical hist or y, pri or 
me dicati o ns/ vacci nati o ns  
X  
 
 
 
 
 
 
C o nc o mita nt 
me dicati o ns/ vacci nati o ns  ( b) 
X  
X  
X ( d) 
X ( d) 
X  
X  
X  
C o m plete p h ysical e xa mi nati o n (c) 
X  
 
X ( d) 
 
X  
 
 
T ar gete d p h ysical e xa mi nati o n (e) 
 
X  
 
X ( d) 
 
X  
X  
Vital si g ns (f) 
X  
X  
X ( d) 
X ( d) 
X  
X  
X  
Pre g na nc y test ( uri ne) ( g) 
X  
 
X ( d) 
 
X  
 
 
Pre g na nc y a v oi da nce g ui da nc e ( h) 
X  
X  
X ( d) 
X ( d) 
X  
X  
 
Ra n d o mizati o n  
X  
 
 
 
 
 
 
C hec k criteria f or 
dela y of trial 
vacci ne 
a d mi nistrati o n  
Gr o u p 1  
 
 
X  
 
X  
 
 
Gr o u p 2  
 
 
 
 
X  
 
 
C hec k 
c o ntrai n dicati o ns 
f or trial vacci ne 
a d mi nistrati o n  
Gr o u p 1  
X  
 
X  
 
X  
 
 
Gr o u p 2  
X  
 
 
 
X  
 
 
Bl o o d c ollecti o n 
f or 
i m m u n o ge nicit y 
testi n g (i) 
Gr o u p 1 –  De n g ue 
ne utralizi n g 
a nti b o dies ( 5 m L)  
X  
 
 
X  
 
 
 
Gr o u p 1 –  H P V 
ne utralizi n g 
a nti b o dies ( 5 m L)  
X  
 
 
 
 
X  
 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 2 6  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
Visits  
1  
2  
3  
4  
5  
6  
7  
D a y  
D a y 1  
D a y 
3 0  
D a y 9 0  
D a y 
1 2 0  
D a y 1 8 0  
D a y 
2 1 0  
D a y 
3 6 0  
M o nt h  
M 0  
M 1  
M 3  
M 4  
M 6  
M 7  
M 1 2 
( E T) ( a) 
Gr o u p 2 –  H P V 
ne utralizi n g 
a nti b o dies ( 5 m L)  
X  
 
 
 
 
X  
 
Vacci nati o n wit h T D V  
X ( d) 
 
X ( d) 
 
 
 
 
Vacci nati o n wit h 9 v H P V  vacci ne  
X  
 
 
 
X  
 
 
P ost -vacci nati o n 
o bser vati o n (j)  
T D V vacci ne  
X ( d) 
 
X ( d) 
 
 
 
 
9 v H P V vacci ne  
X  
 
 
 
X  
 
 
Diar y car d 
distri b uti o n ( k) 
Gr o u p 1  
X  
 
X  
 
 
 
 
Gr o u p 2  
X  
 
 
 
 
 
 
Diar y car d 
re vie w/c ollecti o n 
of s olicite d l ocal 
(i nj ecti o n site) 
reacti o ns a n d 
s yste mic A Es 
Gr o u p 1  
 
X  
 
X  
 
 
 
Gr o u p 2  
 
X  
 
 
 
 
 
A Es (l)  
X  
X  
X ( d) 
X ( d) 
 
 
 
S A Es, A Es lea di n g t o I P wit h dra wal or 
trial disc o nti n uati o n ( m) 
X  
X  
X  
X  
X  
X  
X  
N ote: 9 v H P V = Rec o m bi na nt 9 -vale nt h u ma n pa pill o ma vir us vacci ne; A E =a d verse e ve nt, E T =earl y ter mi nati o n, 
M = m o nt h, S A E =seri o us a d verse e ve nt, T D V = De n g ue T etra vale nt Vacci ne ( Li ve, Atte n uate d); V = visit.  
N ote: w he n a site visit ca n n ot be carrie d o ut d ue t o t he c or o na vir us disease 2 0 1 9 ( C O VI D -1 9 ) pa n de mic, alter nati ve 
met h o ds of c o ntact (e. g tele p h o ne c o ntact) will be ma de f or s u bj ects w h o are still u n der m o nit ori n g f or safet y 
re p orti ng.  
F o ot n otes:  
a) T he fi nal (e n d of trial) visit will be perf or me d o n Da y 3 6 0 ( M 1 2). If a s u bj ect ter mi nates earlier, t he fi nal (e n d of 
trial) visit pr oce d ures s h o ul d be perf or me d at t heir last trial visit, if p ossi ble. F or all s u bj ects recei vi n g trial 
vacci ne(s), t he i n vesti gat or m ust c o m plete t he “ E n d of Trial” e C R F pa ge.  
b)  All me dicati o ns a n d vacci ne hist or y fr o m 1 m o nt h ( mi ni m u m 2 8 da ys) pri or t o a d mi nistrati o n of eac h d ose of trial 
vacci ne(s) u p t o 1 m o nt h ( mi ni m u m 2 8 da ys) t hereafter, ster oi ds a n d i m m u n osti m ula nts wit hi n 6 0  da ys pri or t o 
Da y 1 ( M 0), i m m u n o gl o b uli ns a n d bl o o d pr o d ucts wit hi n 3 m o nt hs pri or t o Da y 1 ( M 0), a n d i m m u n os u p pressi ve 
t hera p y wit hi n 6 m o nt hs pri or t o Da y 1 ( M 0). 
c) P h ysical e xa mi nati o n i ncl u di n g meas ure me nt of wei g ht a n d hei g ht; b o d y mass i n de x will be calc ulate d 
a ut o maticall y.  
d)  O nl y a p plica ble f or s u bj ects i n Gr o u p 1 .  
e) S u bj ects ma y u n der g o a brief s y m pt o m -directe d p h ysical e xa mi nati o n. Cli nicall y si g nifica nt c ha n ges fr o m t he 
baseli ne e xa mi nati o n s h o ul d be rec or de d i n t he s u bj ect’s s o urce d oc u me nts a n d e C R F. 
f) 
Vital si g ns i ncl u di n g ( b ut n ot li mite d t o) t he meas ure me nt of s yst olic bl o o d press ure/ diast olic bl o o d press ure, 
heart rate, a n d b o d y te m perat ure.  
g)  F or fe male s u bj ects of c hil d beari n g p ote ntial,  a pre g na nc y test will be perf or me d a fter i nf or me d c o nse nt a n d 
pe diatric asse nt is o btai ne d.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 2 7  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
h)  Fe male s u bj ects will be pr o vi de d wit h i nf or mati o n o n acce pt a ble met h o ds of c o ntrace pti o n as part of t he s u bj ect 
i nf or me d c o nse nt pr ocess a n d will b e as ke d t o si g n a c o nse nt f or m stati n g t hat t he y u n derst a n d t he re q uire me nts 
f or a v oi da nce of pre g na nc y a n d d o nati o n of o va. S u bj ects will recei ve c o nti n ue d g ui da nce wit h res pect t o t he 
a v oi da nce of pre g na nc y as part of t he trial pr oce d ures, a n d fe male s u bj ects of c hil d beari n g p ote ntial w h o are 
se x uall y active will be re mi n de d d uri n g trial visits t o a d here t o acce pta ble c o ntrace pti ve met h o ds u p t o 6 wee ks 
after t he last d ose of 9 v H P V ( Da y  1 8 0  [ M 6]) + 6 wee ks).  
i) 
T he bl o o d sa m ple o n Da y 1 ( M 0) s h o ul d be ta ke n pri or t o trial vacci nati o n. T he bl o o d sa m ple o n Da y 1 2 0 ( M 4) 
a n d Da y 2 1 0 ( M 7) f or Gr o u p 1 s h o ul d be ta ke n at least 2 9 da ys after t he trial vacci ne vacci nati o n o n Da y 9 0 ( M 3) 
a n d Da y 1 8 0 ( M 6), res pecti vel y, a n d t he bl o o d sa m ple o n Da y 2 1 0 ( M 7) f or Gr o u p 2 s h o ul d be ta ke n at least 
2 9  da ys after t he trial vacc i ne vacci nati o n o n Da y 1 8 0 ( M 6). 
j) 
After eac h trial vacci nati o n, T D V a n d/ or 9 v H P V vacci ne ( Gr o u p 1 a n d 2) o n Da y 1 ( M 0), t he sec o n d d ose of T D V 
o n Da y 9 0 ( M 3) ( Gr o u p 1) a n d t he sec o n d d ose of 9 v H P V ( Gr o u p 1 a n d 2) o n Da y 1 8 0 ( M 6), t he s u bj ect will be 
o bser ve d f or at least 3 0 mi n ut es i ncl u di n g o bser vati o n f or s olicite d l ocal (i nj ecti o n site) reacti o ns, s olicite d 
s yste mic A Es (i ncl u di n g b o d y te m perat ure meas ure me nt), a n d u ns olicite d A Es .  
k)  Diar y ( pa p er or electr o nic) car ds will b e use d f or t he c ollecti o n of:  
1.  S ol icite d l ocal (i nj ecti o n site) reacti o ns f or 7 da ys after T D V a n d 9 v H P V trial vacci nati o n ( da y of 
vacci nati o n  + 6 da ys) o n Da y 1 ( M 0) a n d Da y 9 0 ( M 3). C ollecti o n starti n g o n Da y 1 ( M 0) will be f or 
b ot h i nj ecti o n sites a n d f or s u bj ects i n Gr o u ps 1 a n d 2, a n d  c ollecti o n starti n g o n Da y 9 0 ( M 3) will o nl y 
be f or s u bj ects i n Gr o u p 1 after t he sec o n d T D V d ose. If s olicite d l ocal A Es c o nti n ue  o n Da y 8 f oll o wi n g 
eac h trial vacci nati o n ( o n Da y 1 ( M 0) [ Gr o u p 1 a n d 2] a n d o n Da y 9 0 ( M 3) [ Gr o u p 1 o nl y]), rec or d t he 
e xten de d i nf or mati o n o n t he A d verse E ve nt e C R F.  
2.  S olicite d s yste mic A Es f or 1 4 da ys after T D V a n d 9 v H P V trial vacci nati o n (t he da y of vacci nati o n + 1 3 
da ys) o n Da y 1 ( M 0) a n d Da y 9 0 ( M 3) . C ollecti o n starti n g o n Da y 1 ( M 0) will be f or b ot h i nj ecti o n sites 
a n d f o r s u bj ects i n Gr o u ps 1 a n d 2, a n d c ollecti o n starti n g o n Da y 9 0 ( M 3) will o nl y be f or s u bj ects i n 
Gr o u p 1 after t he sec o n d T D V d ose. If s olicite d s yste mic A Es c o nti n ue o n Da y 1 5 f oll o wi n g eac h trial 
vacci nati o n ( o n Da y 1 ( M 0) [ Gr o u p 1 a n d 2] a n d o n Da y 9 0 ( M 3) [ Gr o u p 1 o nl y]), rec or d t he e xte n de d 
i nf or mati o n o n t he A d verse E ve nt e C R F. T he i n vesti gat or will cate g orize e ve nts b y se verit y ( mil d, 
m o derate or se vere) a n d will assess ca usalit y t o vacci ne a d mi nistrati o n f or s olicite d s yste mic A Es 
(relate d or n ot relate d). 
l) 
U ns olicite d A Es ( n o n -seri o us a n d seri o us) f or 2 8 da ys (i ncl u di n g t he da y of vacci nati o n) after T D V a n d t he first 
9 v H P V vacci nati o n will be c ollecte d b y i nter vie w a n d rec or de d f or all s u bj ects o n Da y 1 ( M 0), Da y 3 0 ( M 1), Da y 
9 0 ( M 3) a n d Da y 1 2 0 ( M 4 ). T he i n vesti gat or will cate g orize e ve nts b y se verit y ( mil d, m o d erate or se vere) a n d 
will assess ca usalit y t o vacci ne a d mi nistrati o n (relate d or n ot relate d).  
m)  A Es lea di n g t o disc o nti n uati o n or wit h dra wal will be c ollecte d f or t he trial d urati o n. S A Es wil l be c ollecte d fr o m 
t he ti me t he s u bj ect is a d mi nist ere d t he trial vacci ne(s) ( Da y 1 [ M 0]) u p t o Da y 3 6 0 ( M 1 2). S A Es will be re p orte d 
t o t he s p o ns or wit hi n 2 4 h o urs of t he i n vesti gat or bec o mi n g a ware of t he e ve nt.  
 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 2 8  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
3. 0  
T RI A L R E F E R E N C E I N F O R M A TI O N  
3. 1  
Tri al -Rel ate d Res p o nsi bilities  
T he s p o ns or will perf or m all trial -relate d acti vities wit h t he e x ce pti o n of t h ose i de ntifie d i n t he 
Trial -Relate d Res p o nsi bilities te m plate. T he ve n d ors i de ntifie d i n t he te m plate f or s pecific 
trial-relate d acti vities will perf or m t hese acti vities i n f ull or i n part ners hi p wit h t he s p o ns or.  
3. 2  
Pri nci p al I n vesti g at or/ C o or di n ati n g I n vesti g at or  
Selecti o n criteria f or t he pri nci pal i n vesti gat or ( PI)  will i ncl u de si g nifica nt k n o wle d ge of t he tri al 
pr ot oc ol, t he i n vesti gati o nal vacci n e, t heir e x pertise i n t he t hera p e utic area a n d t he c o n d uct of 
cli nical researc h as well as trial partici pati o n. Ta k e da will select a si g n at or y i n vesti gat or fr o m t he 
i n vesti gat ors w h o p artici pate i n t he st u d y. T h e si g nat or y i n v estigat or will be re q uir e d t o re vie w 
a n d si g n t he cli nical pr ot oc ol. T he si g n at or y i n vesti gat or  will als o be re q uir e d t o re vie w a n d si g n 
t he cli nical st u d y re p ort ( C S R) a n d b y d oi n g s o a grees  t hat it acc uratel y d escri bes t he res ults of t he 
trial. 
 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 2 9  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
3. 3  
List of A b br e vi ati o ns  
9 v H P V  
Rec o m bi na nt 9 -vale nt h u ma n pa pill o ma vir us vacci ne  
A E  
A d verse e ve nt  
A N C O V A  
A nal ysis of c o vari a nce  
CI  
C o nfi de nce i nter val  
C O VI D -1 9  
C or o na vir us disease 2 0 1 9  
C S R  
Cli nical st u d y re p ort  
C Y D -T D V  
C hi meric yell o w fe ver vir us -de n g ue vir us t etra val e nt de n g ue vacci ne 
D E N V  
Wil d t y pe d e n g ue vir us  
D E N V -1, -2, -3, -4  
Wil d t y pe d e n g ue vir us s er ot y p es 1, 2, 3, a n d 4  
D H F  
De n g ue he m orr ha gic fe v er  
D M C  
Data M o nit ori n g C o m mittee  
D S S  
De n g ue s h oc k s y n dr o me  
E  
E n vel o pe  
E C G  
Electr ocar di o gra m  
e C R F 
Electr o nic case re p ort f or m  
F A S  
F ull a nal ysis set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d cli nical practice  
G M T  
Ge o metric mea n titer  
HI V  
H P V  
H u ma n i m m u n o deficie nc y vir us  
H u ma n pa pill o ma vir us  
I B 
I n v esti gat or’s br oc h ure 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or 
P har mace uticals f or H u m a n Use  
I E C 
I n d e pe n de nt Et hics C o m mittee 
I g G B A 
I m m u n o gl o b uli n G bi n di n g ass a y 
I M 
I ntr a m usc ular 
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
I nteracti ve res p o nse t ec h n ol o g y 
J E 
J a pa nese e nce p halitis  
L A R  
Le gall y a ut h orize d re pres e ntati ve  
M  
M o nt h  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M H R A  
Me dici nes a n d Healt hcare Pr o d ucts Re g ulat or y A ge n c y of U nite d 
Ki n g d o m  
M N T
5 0 
Micr o ne utralizati o n test 5 0 %  
NI  
N o n -i nferi orit y 
P D K  
Pri mar y d o g ki d ne y  
PI  
Pri nci pal i n vesti gat or  
PI P  
Pe diatric i n vesti gati o n pla n  
P M D A  
P har mace uticals a n d Me dical De vices A ge nc y of J a pa n  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 3 0  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
P P S  
Per -pr ot oc ol set  
pr M  
Pre -me m bra n e  
P T  
Preferre d ter m  
Q T L  
Q ualit y t olera nce li mits  
S A E  
Seri o us a d verse e ve nt  
S A G E  
Strate gic A d vis or y Gr o u p of E x perts o n I m m u nizati o n  
S A P  
Statistical a nal ysis pla n  
S C  
S u bc uta ne o us  
S O C  
S yste m or ga n class  
S U S A R  
S us pecte d u ne x pecte d seri o us a d verse reacti o n  
T D V  
De n g ue Tetra val e nt Vacci ne ( Li v e, Atte n uat e d), als o k n o w n as T A K -0 0 3  
T D V -1  
De n g ue ser ot y p es 2/ 1 rec o m bi na nt strai n  
T D V -2  
M olec ularl y c h aracterize d, atte n uate d de n g u e ser ot y pe 2 strai n  
T D V -3  
De n g ue ser ot y p es 2/ 3 rec o m bi na nt strai n  
T D V -4  
De n g ue ser ot y p es 2/ 4 rec o m bi na nt strai n  
W H O  
W orl d Healt h Or ga nizati o n  
W N  
West Nile  
Y F  
Yell o w fe ver  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 3 1  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
3. 4  
C or p or ate I de ntific ati o n  
T V  
Ta ke da V acci nes, I nc.  
 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 3 2  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
4. 0  
I N T R O D U C TI O N 
4. 1  
B ac k gr o u n d  
De n g ue fe ver is ca use d b y i nfecti o n wit h t he wil d t y pe d e n g ue vir us ( D E N V), a ri b o n ucl eic aci d 
vir us t hat occ urs as 4 rec o g niz e d ser ot y pes, D E N V -1, D E N V -2, D E N V -3, or D E N V -4. T h ese 
de n g u e vir uses are tr a ns mitte d t o h u ma n b y m os q uit oes ( pri maril y A e des a e gy pti ) a n d are e n de mic 
i n Asia, Ce ntral a n d S o ut h A merica, t he Cari b bea n, t he Pacific Isla n ds, a n d parts of Africa. T here 
are a n esti mate d 3 9 0 milli o n de n g ue i nf ecti o ns per year w orl d wi de, w hi c h is m ore t ha n 3 ti mes t he 
pre vi o us W orl d Healt h Or ga niz ati o n ( W H O) esti mate of 5 0 t o 1 0 0 milli o n cases [ 3 ]. E ver y year, 
ar o u n d 5 0 0, 0 0 0 cases of de n g u e he m orr ha gic fe ver ( D H F) re q uire h os pitali zati o n wit h a n 
esti mate d deat h rat e of  2. 5 %, pri maril y i n c hil dre n. It is esti mate d t hat 3. 9 billi o n pe o ple are at ris k 
of de n g ue i nf ecti o n [ 4 -7 ]. 
De n g ue fe ver is cli nic all y defi ne d as a n ac ut e fe brile ill ness wit h 2 or m ore of t he f oll o wi n g 
ma nifestati o ns: hea dac he, retr o -or bital p ai n, m yal gia, art hral gia, ras h, he m orr ha gic 
ma nifestati o ns, or le u k o p e nia, a n d occ u rre nce at t he sa me l ocati o n a n d ti m e as ot her c o nfir me d 
cases of d e n g ue fe ver. T he m ost se vere f or ms of de n g u e i nfecti o n –  D H F a n d de n g ue s h o c k 
s y n dr o me ( D S S) –  are life t hreate ni n g. Pri mar y i nfecti o n wit h a n y o ne of t h e 4 d e n g ue s er ot y pes is 
t h o u g ht t o res ult i n life-l o n g pr otecti o n fr o m r e-i nfecti o n b y t he sa me s er ot y p e, b ut d o es n ot 
pr otect a gai nst a s ec o n dar y i nf ecti o n b y o ne of t h e ot her 3 de n g ue s er ot y pes a n d ma y lea d t o a n 
i ncreas e d ris k of se v ere disease ( D H F/ D S S) [6 -9 ]. 
Treat me nt of de n g ue fe ver is base d s olel y o n si g ns a n d s y m pt o ms, wit h fl ui d re place m e nt re q uire d 
f or he m orr h a gic or s h o c k cases. A n a nti viral t hera p y f or D E N V i nfecti o n is n ot yet a vaila ble. 
Pre ve nti ve meas ur es t hat rel y o n m os q uit o c o ntr ol a n d i n di vi d ual pr otecti o n are of li mite d 
effic ac y, c o m ple x t o i m ple me nt a n d q uesti o na ble i n ter ms of c ost -effecti v e ness. T here is a great 
u n met gl o bal p u blic healt h nee d f or a safe a n d effecti ve vacci ne t o re d u ce t h e m or bi dit y a n d 
m ortalit y ass ociat e d wit h de n g u e diseas e. Vacci ne de vel o p me nt has f o c use d o n tetra vale nt 
vacci nes t hat pr o vi de pr otecti o n a gai nst all 4 de n g ue ser ot y pes si m ulta ne o usl y si nce all 4 de n g ue 
ser ot y p es c o m m o nl y c o-circ ulate i n e n de mic areas [ 4 -1 0 ]. A first rec o m bi na nt de n g ue vacci ne 
(c hi meric yell o w fe ver vir us-de n g ue vir us t etra val e nt de n g ue vacci ne [ C Y D -T D V]) has bee n 
a p pr o ve d si nce 2 0 1 5 i n se veral Asi a n a n d Lati n A merica n c o u ntries [ 1 1 ] as well as i n t he U nite d 
States a n d i n t he E ur o pea n U ni o n. Cli nical data i n dicate a n u nfa v ora ble ris k -be nefit pr ofile f or 
c hil dre n a ge d < 9 years wit h t his first a p pr o ve d vacci ne.  A d diti o nall y, vacci ne effi cac y was 
differe nt b et wee n s er ot y p es a n d de pe n d e d o n de n g ue pre -e x p os ure stat us  [1 2 ]. M ore rece nt 
a nal ys es f o u n d t hat pe o pl e w h o ha d n ot bee n i nfecte d b y d e n g ue vir us bef ore vacci nati o n ha d a 
hi g her ris k of getti n g se v ere dise ase w he n t h e y were i nfecte d wit h de n g ue vir us after vacci n ati o n 
wit h C Y D -T D V [ 1 3 ]. I n a re vis e d Strate gic A d vis or y Gr o u p of E x perts o n I m m u nizati o n ( S A G E) 
rec o m me n dati o n i n A pril 2 0 1 8, t he S A G E c o ncl u de d t hat f or c o u ntri es c o nsi deri n g C Y D-T D V 
vacci nati o n as p art of t heir de n g ue c o ntr ol pr o gra m, a “ pre -v acci nati o n scree ni n g strat e g y” w o ul d 
be t he  preferre d o pti o n, i n w hic h o nl y d e n g ue -s er o p ositi ve pers o ns are v acci nate d [1 4 ]. 
He nce, t h ere is a c o nti n ue d u n met p u blic healt h n ee d f or s afer a n d m or e efficaci o us de n g u e 
vacci nes [ 1 5 ]. 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 3 3  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
De n g ue Tetr a v ale nt V a cci ne ( Li ve, Atte n u ate d) ( T D V) - B ac k gr o u n d:  
T he i n vesti gati o nal vacci ne T D V, als o k n o w n as T A K -0 0 3, c o nsists of 1 m olec ula rl y 
c haracteriz e d, atte n u ate d de n g u e vir us ser ot y p e 2 strai n de n ote d as t he de n g ue vir us ser ot y pe 2 
bac k b o ne  a n d 3 rec o m bi na nt de n g ue vir us strai ns e x pressi n g s urface a nti ge ns c orres p o n di n g t o 
D E N V ser ot y p es 1 -4. T h e de n g ue vir us s er ot y pe 2 bac k b o ne is bas e d u p o n t he atte n uate d 
la b orat or y-d eri ve d D E N V -2 vir us strai n, ori gi nall y is olate d at M a hi d ol U ni versit y, Ba n g k o k, 
T haila n d a n d ge n erate d b y 5 3 serial passa ges i n pri mar y d o g ki d ne y ( P D K) cells 
( D E N V-2  P D K -5 3)  [1 6 ]. T he rec o m bi na nt, atte n uate d vacci ne strai ns f or de n g u e ser ot y p es  1, 
3  a n d 4 were e n gi ne ere d b y s u bstit uti n g t he str uct ural ge nes, pre -me m bra n e ( pr M) a n d 
e n vel o pe ( E), of t he d e n g ue vir us ser ot y pe 2 b ac k b o ne  wit h t he pr M a n d E ge nes of t he D E N V 
vir us strai ns, D E N V -1  1 6 0 0 7, D E N V -3 1 6 5 6 2 or D E N V -4 1 0 3 6 vir us, res pecti vel y [ 1 7 ]. T h us, 
T D V is c o m prise d of 4 d e n g u e vir u s strai ns: de n g ue vir us ser ot y pe 1 (li ve, atte n uate d), d e n g ue 
vir us ser ot y p e  2 (li ve, att e n uate d), d e n g ue vir us ser ot y pe 3 (li ve, atte n u ate d), a n d de n g ue vir us 
ser ot y p e 4 (li ve, atte n u at e d). All 4 de n g ue vir us s er ot y p es are pr o d u ce d i n Ver o cells b y 
rec o m bi na nt de o x yri b o n ucleic aci d ( D N A) tec h n ol o g y. De n g u e vir us ser ot y pes 1, 3, a n d 4 
pr o d ucts c o ntai n ge n eticall y m o difie d or ga nis ms . S pecificall y, ge nes of ser ot y pe -s p ecific s urface 
pr otei ns are e n gi neere d i nt o t he de n g u e vir us ser ot y pe 2 b ac k b o ne . 
N o ncli nica l st u dies carrie d o ut i n mice a n d n o n h u ma n pri mates ha ve d e m o nstrate d a satisfact or y 
safet y, i m m u n o ge nicit y, a n d effi cac y pr ofile of T D V . A d diti o nall y, dat a fr o m c o m plete d p hase 1 
a n d p hase 2 cli nic al trials i n h u ma ns ha ve s h o w n s atisfact or y react o ge nicit y , safet y a n d 
i m m u n o ge nicit y pr ofiles of T D V i n healt h y a d ults i n n o n-e n de mic areas as well as i n healt h y 
a d ults a n d c hil dre n i n e n de mic areas i n Asia a n d Lati n A merica. O n g oi n g a n d c o m plete d p has e 2 
cli nical trials ha ve e n a ble d t he selecti o n of a fi nal T D V  d ose (l y o p hilize d f or m ulati o n), a n d a 
2 -d ose vacci nati o n re gi m e n ( 2 si n gl e d oses) a d mi nistere d 3 m o nt hs (ie,  9 0  d a ys) a part b y 
s u bc uta ne o us ( S C) i njecti o n f or use i n t he o n g oi n g pi v otal pr o gra m. Res ults fr o m a n i nteri m 
a nal ysis f or Part 1 of t he p hase 3 t rial D E N-3 0 1  s h o we d t hat t he pri mar y efficac y e n d p oi nt was 
met. I n p artic ular, t h e dat a de m o nstrate d vacci n e efficac y of 2 d oses of T D V i n pre ve nti n g 
vir ol o gicall y -c o nfir me d de n g u e fe v er i n d uce d b y a n y d e n g ue ser ot y pe occ urri n g fr o m 3 0  da ys 
p ost -sec o n d vacci nati o n ( Da y 1 2 0 [ M o nt h 4 ( M 4)]) u ntil t he e n d of Part 1.  
T he c urre nt i n vesti gat or’s br oc h ure (I B) pr o vi des a d diti o nal pr o d uct i nf or mati o n a n d a m ore 
detaile d re vie w of n o ncli nical st u dies a n d cli nical trials.  
4. 2  
R ati o n ale f or t he Pr o p ose d Tri al  
T he W H O rec o m me n ds t hat ne w vacci nes s h o ul d be i ntr o d uce d acc or di n g t o e xisti n g nati o nal 
i m m u nizati o n pr o gra ms [1 8 ]. Rec o m bi na nt 9 -vale nt h u ma n pa pill o ma vir us  ( H P V) vacci ne is 
rec o m me n de d i n a 2-d os e sc he d ule 6 t o 1 2 m o nt hs a part i n s u bjects 9 t hr o u g h 1 4 years of a ge. 
F urt her, if t he sec o n d d os e is a d mi nistere d earlier t ha n 5 m o nt hs after t he first d ose, t he n a t hir d 
d ose s h o ul d be a d mi nistere d at least 4 m o nt h s aft er t he sec o n d d os e [1 9 ]. 
Ma n y si milarities e xist bet wee n t he pr o p ose d vacci nati o n sc he d ule f or T D V a n d t he a p pr o ve d 
sc he d ule f or 9 -vale nt H P V ( 9 v H P V ) vacci ne, i ncl u di n g t he o verla p pi n g tar get a ge gr o u p a n d t he 
p ote ntial deli ver y t hr o u g h sc h o ol i m m u nizati o n pr o gra ms.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 3 4  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
I n or der t o a v oi d barriers t o t he i ncl usi o n of T D V i n r o uti ne nati o nal vacci n ati o n pr o gra ms, t he 
i m pact of T D V o n vacci n es a d mi nistere d via s uc h pro gra ms nee ds t o be e x a mi ne d. T his is 
partic ularl y rel e va nt f or l o w -i nc o me c o u ntries w here t he c ost of a sta n dal o ne vacci n ati o n c o ul d be 
t o o hi g h, a n d p ote ntiall y u n der mi ne T D V u pta k e, if i ncl usi o n i n r o uti ne vacci ne sc h e d ules were 
n ot p ossi ble.  
Wit h t his t rial, we ai m t o pr o vi de i m m u n o ge nicit y a n d safet y d ata o n t he c o-a d mi nistrati o n of 
9 v H P V vacci ne wit h T D V i n healt h y s u bjects a ge d ≥9 t o < 1 5  years at t he ti me of i nf or me d c o nse nt 
i n or der t o facilitate i ncl usi o n i nt o esta blis he d vacci nati o n sc he d ules a n d miti gate t he 
af ore -me nti o ne d pr o ble ms. I n t his trial, a p pr o xi matel y 6 1 4 s u bjects are pla n ne d t o be e nr olle d. 
T he trial will be c o n d uct e d i n acc or da nce wit h t he pr ot oc ol, I nter nati o nal C o u ncil f or 
Har m o nisati o n of Tec h nical Re q uire me nts f or P har mace uticals f or H u ma n Use ( I C H) E 6 ( R 2), 
a n d G o o d Cli nical Practi ce ( G C P ) g ui deli nes [ 2 ], a n d a p plica ble re g ulat or y re q uire me nts [1 ]. 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 3 5  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
5. 0  
T RI A L O B J E C TI V E S A N D E N D P OI N T S  
5. 1  
O bjecti ves  
5. 1. 1  Pri m ar y O bjecti ve  
T o de m o nstrate t he n o n -i nferi orit y ( NI) of t he i m m u ne res p o nse (i n ter ms of ge o metri c mea n titers 
[ G M Ts]) t o 2 d oses of 9 v H P V vacci ne, 1 c o -a d mi nistere d wit h T D V, c o m p are d wit h 2  d oses of 
9 v H P V vacci ne a d mi nistere d al o n e.  
5. 1. 2  Sec o n d ar y O bjecti ves  
I m m u n o ge nicit y 
•  T o descri be t he i m m u ne res p o nse t o H P V (i n ter ms of ser ores p o nse) i n s u bj ects a d mi nistere d 
2  d oses of 9 v H P V vacci ne, 1 c o -a dmi nistere d  wit h T D V, c o m pare d wit h s u bjects a d mi nistere d 
2 d oses of 9 v H P V vacci n e al o ne.  
•  T o descri be t he i m m u ne res p o nse t o T D V at 1 m o nt h f oll o wi n g a sec o n d d ose of T D V gi ve n 
3  m o nt hs after t he first d ose of T D V a d mi nistere d c o nc o mita ntl y wit h 9 v H P V vacc i ne. 
Safet y  
•  T o descri be  t he safet y pr ofile after a d mi nistrati o n of T D V c o nc o mita ntl y wit h 9 v H P V vacci ne. 
5. 2  
E n d p oi nts  
5. 2. 1  Pri m ar y E n d p oi nt  
•  Ge o metric mea n titers  f or H P V T y p es 6, 1 1, 1 6, 1 8, 3 1, 3 3, 4 5, 5 2, 5 8 o n Da y 2 1 0 ( M o nt h 7 
[ M 7]). 
5. 2. 2  Sec o n d ar y E n d p oi nts  
I m m u n o ge nicit y 
•  Ser o p ositi vit y rates ( % of s u bjects ser o p ositi ve) f or H P V T y p es 6, 1 1, 1 6, 1 8, 3 1, 3 3, 4 5, 5 2 
a n d 5 8 o n Da y 2 1 0 ( M 7) as meas ure d b y i m m u n o gl o b uli n G bi n di n g assa y (I g G B A) or 
e q ui vale nt assa y.  
•  G M Ts of ne utralizi n g a nti b o dies ( b y micr o ne utrali zati o n test 5 0 % [ M N T
5 0]) f or eac h of t h e 
4  de n g u e ser ot y p es o n D a y 1 2 0 ( M 4).  
•  Ser o p ositi vit y rates ( % of s u bjects ser o p ositi ve) f or eac h of t he 4 de n g u e s er ot y p es a n d f or 
m ulti ple ( 2, 3 or 4) de n g ue ser ot y pes o n D a y 1 2 0 ( M 4).  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 3 6  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
Defi niti o n of ser o p ositi vit y - de n g ue  vir us  
Ser o p ositi vit y is defi ne d as a reci pr ocal ne utralizi n g a nti b o d y titer ≥1 0 f or a n y of t he 4 de n g u e 
ser ot y p es. 
Defi niti o n of ser o p ositi vit y - H P V  
T he mi ni m u m a nti -H P V titer t hat c o nfers pr otecti ve effi cac y h as n ot bee n deter mi ne d.  
Ser o p ositi vit y f or H P V is defi ne d as a n a nti -H P V titer great er t ha n or e q ual t o t he pre -s pecifie d 
ser ostat us c ut-off f or a gi ve n H P V t y p e. Ser o ne gati vit y is d efi ne d as a n a nti -H P V titer less t ha n t he 
pre -s pecifie d ser ostat us c ut-off f or a gi ve n H P V t y pe. T he ser ost at us c ut -o ff is t he a nti b o d y titer 
le vel a b o ve t he assa y’s l o wer li mit of q ua ntificati o n t hat relia bl y disti n g uis hes sera s a m ples 
classifie d b y cli nical li keli h o o d of H P V i nfecti o n a n d p ositi ve or ne gati ve stat us b y pre vi o us 
versi o ns of I g G B A or e q ui vale nt assa y.  
S er u m a nti b o dies t o H P V t y pes 6, 1 1, 1 6, 1 8, 3 1, 3 3, 4 5, 5 2, a n d 5 8 will be meas ure d wit h a n 
I g G B A or e q ui val e nt ass a y. Titers will be re p orte d i n milli-Merc k u nits/ m L wit h t he use of t he 
I g G B A. F or t h e l o wer li mits of q ua ntificati o n a n d ser ostat us c ut-offs  f or eac h of t he 9 v acci n e 
H P V t y pes , ple ase refer t o t he statistical a nal ysis pla n ( S A P). 
Safet y  
•  Fre q u e nc y a n d se verit y of s olicite d l ocal (i njecti o n site) reacti o ns f or 7 da ys ( da y of 
vacci nati o n + 6 d a ys ) ( Gr o u p 2 a n d c ollecte d at eac h i njecti o n site i n Gr o u p 1) a n d s olicite d 
s yste mic a d v erse e ve nts ( A Es) f or 1 4 d a ys ( da y of vacci nati o n + 1 3 da ys) after vacci nati o n  o n  
Da y  1 ( M 0) ( Gr o u p  1 a n d 2) a n d Da y  9 0 ( M 3) ( Gr o u p  1) . 
•  Perce nta ge of s u bjects wit h a n y u ns olicite d A Es f or 2 8 da ys ( da y of vacci nati o n + 2 7 da ys)  after 
vacci nati o n o n D a y  1 ( M 0) ( Gr o u p  1 a n d 2) a n d Da y  9 0 ( M 3) ( Gr o u p  1) . 
•  Perce nta ge of s u bjects wit h seri o us A Es ( S A Es) t hr o u g h o ut t he tri al ( Gr o u p 1 a n d 2) . 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 3 7  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
6. 0  
T RI A L D E SI G N A N D D E S C RI P TI O N  
6. 1  
Tri al Desi g n  
T his is a p hase 3, o pe n -la bel, ra n d o mize d, m ultice nter trial i n 6 1 4 healt h y s u bjects a ge d ≥9 t o 
< 1 5  years i n e n de mic areas f or de n g u e, t o i n vesti gate t he i m m u n o ge nicit y a n d safet y of t he 
c o-a d mi nistrati o n of T D V a n d 9 v H P V vacci ne vs 9 v H P V vacci ne al o ne. S u bjects will be 
ra n d o mize d e q uall y t o 1 of 2 gr o u ps ( 3 0 7 s u bjects per trial gr o u p):  
•  Gr o u p 1: first d oses of 9 v H P V vacci ne + T D V c o -a d mi nistere d o n Da y 1 ( M 0), sec o n d d ose of 
T D V a d mi nistere d o n Da y 9 0 ( M 3), sec o n d d ose of 9 v H P V vacci ne a d mi nistere d o n Da y 1 8 0 
( M 6) 
•  Gr o u p 2: first d ose of 9 v H P V vacci n e a d mi nistere d o n Da y 1 ( M 0), sec o n d d ose of 9 v H P V 
vacci ne a d mi nistere d o n Da y 1 8 0 ( M 6)  
C o nc o mita ntl y a d mi nistere d vacci nes will be i njecte d i nt o o p p osite ar ms. All s u bjects will be 
f oll o we d-u p f or 6 m o nt hs after t he last trial vacci nati o n, s o t he trial d u rati o n will be a p pr o xi matel y 
3 6 0 da ys ( or 1 2 m o nt hs) f or eac h s u bject.  
T he sc he matic of t he trial desi g n a n d bl o o d dra w s c he d ule is i ncl u de d as Fi g ure  6 .a. A sc h e d ule of 
trial pr oce d ures is pr o vi d e d i n Secti o n 2. 1 . 
Fi g ure  6 .a  
Sc he m atic of Tri al Desi g n D E N -3 0 8  
 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 3 8  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
I m m u n o ge nicit y e v al uati o n 
Bl o o d sa m ples f or t he m eas ure m e nt of H P V t otal i m m u n o gl o b uli n G ( Merc k assa y) f or b ot h 
Gr o u ps 1 a n d 2 will be c ollecte d at pre -first vacci nati o n ( Da y 1 [ M 0]) a n d at 1 m o nt h p ost-sec o n d 
9 v H P V vacci nati o n ( Da y 2 1 0 [ M 7]) . 
Bl o o d sa m ples f or t he m eas ure m e nt of de n g ue n e utralizi n g a nti b o dies ( b y M N T 5 0) will be 
c ollecte d f or Gr o u p 1 o nl y at pre -first v acci nati o n ( Da y 1 [ M 0]) a n d at 1 m o nt h p ost-sec o n d T D V 
vacci nati o n ( Da y 1 2 0 [ M 4]).  
Safet y e val uati o n  
Diar y car ds will be dist ri b ute d t o all s u bjects’ le gall y a ut h orize d re prese nt ati ves ( L A R) f or t h e 
rec or di n g of: 
•  S olicite d l ocal (i njecti o n site) reacti o ns f or 7 da ys f oll o wi n g vacci nati o n ( da y of vacci nati o n + 6 
da ys) o n Da y 1 ( M 0) ( Gr o u p 2 a n d c ollecte d at eac h i njecti o n site i n Gr o u p 1) a n d Da y 9 0 ( M 3) 
( Gr o u p 1).  
Reacti o ns will i ncl u de: i njecti o n site pai n, i njecti o n site er yt h e ma a n d i njecti o n site s welli n g. 
•  S olicite d s yst e mic A Es f or 1 4 da ys f oll o wi n g vacci nati o n ( da y of vacci n ati o n + 1 3 da ys) o n 
Da y  1 ( M 0) ( Gr o u p 1  a n d 2) a n d Da y 9 0 ( M 3) ( Gr o u p 1).  
E ve nts will i ncl u de:  (fe v er defi n e d as b o d y te m perat ure ≥3 8. 0° C [ ≥1 0 0. 4° F]) [2 0 ], ast he nia, 
malaise, hea d ac he a n d m yal gia.  
•  U ns olicite d A Es f or 2 8 d a ys f oll o wi n g v acci n ati o n ( da y of vacci nati o n + 2 7 da ys) o n Da y 1 
( M 0) ( Gr o u p 1 a n d 2) a n d Da y 9 0 ( M 3) ( Gr o u p 1). 
•  S A Es will be rec or de d f or t he trial d urati o n ( Gr o u p 1 a n d 2).  
Data will be c ollecte d usi n g a n electr o ni c Case Re p ort F or m (e C R F).  
6. 2  
J u stific ati o n f or Tri al Desi g n, D ose, a n d E n d p oi nts 
T he trial desi g n a n d t he c ollecti o n of s olicite d A Es ( l ocal [i njecti o n site] reacti o ns a n d s yste mic 
A Es) , a n d u ns olicite d A Es (seri o us a n d n o n-s eri o us) f oll o wi n g trial d ose a d mi nistrati o n are 
c o nsiste nt wit h vacci ne e val uati o n trials.  
O n g oi n g a n d c o m plete d p hase 2 trials ha v e e na ble d t he selecti o n of a fi nal T D V d ose (l y o p hilize d 
f or m ulati o n) a n d a 2-d ose vacci nati o n re gi me n 3 m o nt hs a part b y S C i njecti o n f or use i n Ta ke da’s 
de n g u e pi v otal trial pr o gra m.  
T he  trial is o pe n la bel gi ve n t hat t he mai n p ur p os e of t he trial is t o i n vesti gate i m m u n ol o gical 
i nterfere nce f or t he c o-a d mi nistere d trial vacci n es w here bli n di n g is less rel e va nt t ha n f or s afet y 
assess me nts. F urt h er m ore, t he sa m ple siz e of t he trial is c o ns i dere d t o o s mall t o detect safet y iss ues 
a n d t h us d oes n ot s u p p ort a bli n de d desi g n f or t he c urre nt trial. N ot a bl y, t h e safet y pr ofile of t he 
lice nse d 9 v H P V vacci ne is well k n o w n a n d f or T D V a satisfact or y safet y pr ofile has bee n see n i n 
c o m plete d p hase 2 a n d p hase 3 trials.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 3 9  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
T he ti mi n g of t he pri mar y a n d s ec o n dar y e n d p oi nts after vacci nati o n is c o nsiste nt wit h pre vi o us 
trials wit h T D V. De n g ue ne utralizi n g a nti b o dies h a ve bee n ge nerall y acce pte d as t he i m m u ne 
res p o nse e n d p oi nt f or de n g ue v acci ne trials. 
T he a ge ra n ge f or 9 v H P V vacci n e a d mi nistrati o n is acc or di n g t o t he a p pr o ve d prescri bi n g 
i nf or mati o n a n d W H O rec o m me n dati o ns. T he trial p o p ulati o n selecte d t o recei ve eit her or b ot h 
T D V a n d 9 v H P V vacci n es i n t his trial has bee n t h us selecte d beca use t his a ge gr o u p is t he m ost 
li kel y t o recei v e 9 v H P V vacci ne acc or di n g t o t he vacci ne la bel a n d t he W H O, a n d it is i m p orta nt t o 
i nc or p orate t his i nt o e xisti n g vacci nati o n sc he d ul es [1 8 ,1 9 ]. 
Bl o o d sa m pli n g v ol u mes a n d t he pla n ne d sc h e d ul e are c o nsiste nt wit h t he rec o m me n dati o ns 
re gar di n g bl o o d sa m pli n g i n c hil dre n a n d a d oles ce nts fr o m 9 t o 1 5 years [2 1 ,2 2 ]. 
Details relati n g t o t he sa m ple siz e are pres e nte d  i n Secti o n 1 3. 3 . T he rati o nale f or t he pr o p ose d 
trial is gi ve n i n Secti o n  4. 2 . Trial e n d p oi nts are d etaile d i n Secti o n 5. 2 . T he c urre nt I B c o ntai ns 
a d diti o nal i nf or mati o n a n d a  m ore detaile d re vie w of n o n -cli nical st u dies a n d cli nical trials .  
6. 3  
Pl a n ne d D ur ati o n of S u bject’s E x pecte d P arti ci p ati o n i n t he E ntire Tri al  
T he trial d urati o n f or eac h s u bject will be a p pr o xi matel y 3 6 0 d a ys ( or 1 2 m o nt hs) i ncl u di n g trial 
d ose a d mi nistrati o n ( Da y 1 [ M 0], Da y 9 0 [ M 3] a n d Da y 1 8 0 [ M 6] a n d f oll o w -u p t hr o u g h 
Da y  3 6 0  [ M 1 2]). 
6. 4  
Pre m at ure Ter mi n ati o n or S us pe nsi o n of Tri al or I n vesti g ati o n al Site  
6. 4. 1  Criteri a f or Pre m at ure Ter mi n ati o n or S us pe nsi o n of t he Tri al  
T he trial will be c o m plet e d as  pla n ne d u nless o n e or m ore of t he f oll o wi n g criteria t hat re q uire 
te m p orar y s us pe nsi o n or earl y ter mi nati o n of t he trial are s atisfie d. 
•  Ne w i nf or mati o n or ot her e val uati o n r e gar di n g t h e safet y or effi cac y of t he i n vesti gati o nal 
vacci ne t h at i n dicates a c h a n ge i n t he k n o w n ris k/ b e nefit pr ofile, s u c h t hat t he ris k/ be nefit is n o 
l o n ger acce pta ble f or s u bjects partici pati n g i n t he trial. 
•  Si g nifica nt de viati o n fr o m G C P t hat c o m pr o mises t he a bilit y t o ac hie ve t h e pri mar y trial 
o bjecti ves or c o m pr o mis es s u bject s afet y.  
•  T he s p o ns or deci d es t o ter mi nate or s us pe n d t he tri al.  
6. 4. 2  Criteri a f or Pre m at ure Ter mi n ati o n or S us pe nsi o n of I n vesti g ati o n al Sites  
A trial site ma y b e ter mi nate d pre mat urel y or s us pe n de d if t he site (i ncl u di n g t he i n vesti gat or) is 
f o u n d i n si g nifica nt d e viati o n fr o m G C P, pr ot oc ol, or c o ntract ual a gree me nt, is u na ble t o e ns ure 
a de q uate p erf or ma nce of t he trial, or as ot her wise per mitte d b y t he c o ntract ual a gree me nt.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 4 0  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
6. 4. 3  Pr o ce d ures f or Pre m at ure Ter mi n ati o n or S us pe nsi o n of t he Tri al or t he 
P artici p ati o n of I n vesti g ati o n al Site(s) 
I n t he e ve nt t hat t he s p o ns or, a n I nstit uti o nal Re vie w B oar d (I R B)/I n d e pe n de nt Et hics C o m mittee 
(I E C) or re g ulat or y a ut h orit y ele ct t o ter mi nate or s us pe n d t he trial or t he p artici pati o n of a n 
i n vesti gati o nal site, a tri al-s pecific pr oce d ure f or earl y ter mi nati o n or s us pe nsi o n will be pr o vi de d 
b y t he s p o ns or; t he pr oce d ure will be f oll o we d b y a p plica ble i n vesti gati o nal sites d uri n g t he c o urse 
of ter mi nati o n or trial s us pe nsi o n.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 4 1  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
7. 0  
S E L E C TI O N A N D DI S C O N TI N U A TI O N/ WI T H D R A W A L  O F S U B J E C T S  
All e ntr y criteria, i n cl u di n g test r es ults, nee d t o be c o nfir me d pri or t o ra n d o mizati o n.  
7. 1  
I ncl usi o n Criteri a 
S u bject eli gi bilit y is deter mi ne d acc or di n g t o t he f oll o wi n g criteria:  
1.  T he s u bject is a ge d ≥9 t o < 1 5  years.  
2.  Male or fe m ale.  
3.  S u bjects w h o are i n g o o d healt h at t he ti me of e ntr y i nt o t he trial as d eter mi ne d b y m e dical 
hist or y, p h ysical e x a mi nati o n (i ncl u di n g vital si g ns), a n d t he cli nical j u d g me nt of t he 
i n vesti gat or. 
4.  T he s u bject has si g ne d a n d date d a n ass e nt f or m a n d/ or pare nt(s) or L A R(s)  ha ve si g ne d a n d 
date d a writte n i nf or me d c o nse nt f or m, i ncl u di n g a n y re q uire d pri v ac y a ut h orizati o n f or m, 
pri or t o t he i nitiati o n of a n y trial pr o ce d ures, aft er t he nat ure of t h e trial has bee n e x plai ne d 
acc or di n g t o l ocal re g ulat or y re q uire m e nts.  
5.  S u bjects w h o ca n  c o m pl y wit h trial pr oce d ures a n d are a v aila ble f or t he d urati o n of f oll o w -u p.  
7. 2  
E xcl usi o n Criteri a  
A n y s u bject w h o meets a n y of t he f oll o wi n g criteria will n ot q ualif y f or e ntr y i nt o t he trial:  
1.  S u bjects wit h a n ele vate d oral te m perat ure ≥3 8° C ( ≥1 0 0. 4° F) wi t hi n 3 da ys of t he i nte n de d 
date of vacci nati o n (c o nsi der w het her a p plica bl e as a n e x cl usi o n criteri o n or criteri o n f or 
dela y, see Secti o n 7. 3 ). 
2.  S u b jects wit h c o ntrai n dicati o ns, war ni n gs a n d/ or preca uti o ns t o vacci nati o n wit h 9 v H P V 
vacci ne as s pecifi e d wit hi n t he prescri bi n g i nf or m ati o n.  
3.  K n o w n h y p erse nsiti vit y or aller g y t o a n y of t he tri al vacci ne c o m p o ne nts (i ncl u di n g e x ci pie nts 
of t he trial vacci ne s). 
4.  S u bjects wit h be ha vi oral or c o g niti ve i m pair me nt or ps yc hiatric disease t hat, i n t he o pi ni o n of 
t he i n vesti gat or, m a y i nterfere wit h t he s u bject’s a bilit y t o partici pate i n t he trial. 
5.  S u bjects  wit h a n y hist or y of pr o gressi ve or se vere ne ur ol o gi c dis or der, seiz ure dis or der or 
ne ur o -i nfla m mat or y dise ase (e g, G uillai n-Barré s y n dr o me).  
6.  S u bjects wit h a hist or y of or a n y c urre nt ill ness t hat, i n t he o pi ni o n of t he i n vesti gat or, mi g ht 
i nterfere wit h the res ults of t he trial or p ose a d diti o nal ris k t o t he s u bjects d ue t o partici pati o n 
i n t he trial. 
7.  K n o w n or s us pect e d i m pair me nt/alterati o n of i m m u ne f u ncti o n, i ncl u di n g:  
a)  C hr o nic use of oral ster oi ds (e q ui vale nt t o 2 0 m g/ d a y pre d nis o ne ≥1 2 w ee ks/ ≥2 m g/ k g 
b o d y wei g ht/ da y pre d nis o ne ≥2 wee ks) wit hi n 6 0 da ys pri or t o Da y 1 ( M 0) ( use of i n hale d, 
i ntra nasal, or t o pical c ortic oster oi ds is all o we d). 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 4 2  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
b)  Recei pt of pare nteral ster oi ds (e q ui vale nt t o 2 0 m g/ da y pre d nis o ne ≥1 2 wee ks/ ≥2 m g/ k g 
b o d y w ei g ht/ da y pre d nis o ne ≥2 wee ks) wit hi n 6 0 da ys pri or t o Da y 1 ( M 0).  
c)  A d mi nistrati o n of i m m u n o gl o b uli ns a n d/ or a n y bl o o d pr o d ucts wit hi n t he 3 m o nt hs pri or 
t o Da y 1 ( M 0) or pla n n e d a d mi nistrati o n d uri n g t he trial. 
d)  Recei pt of i m m u n osti m ula nts wit hi n 6 0 da ys pri or t o Da y 1 ( M 0).  
e)  I m m u nos u p pr essi ve t hera p y s u c h as a nti -ca ncer c he m ot hera p y or ra diati o n t hera p y wit hi n 
6 m o nt hs pri or t o Da y 1 ( M 0).  
f) H u ma n i m m u n o deficie nc y vir us ( HI V) i nf ecti o n or HI V -relate d dise ase. 
g)  He patitis B vir us i nfecti o n.  
h)  He patitis C vir us i nfecti o n.  
i) Ge netic i m m u n o def icie n c y. 
8.  A b n or malities of s ple nic or t h y mic f u ncti o n.  
9.  S u bjects  wit h a k n o w n blee di n g diat hesis, or a n y c o n diti o n t hat ma y be ass o ciate d wit h a 
pr ol o n ge d blee di n g ti me.  
1 0.  S u bjects  wit h a n y seri o us c hr o nic or pr o gressi ve disease acc or di n g t o t he j u d g me nt of t he 
i n vesti gat or (e g, ne o plas m, he mat ol o gic mali g na n cies, i ns uli n de pe n de nt di a betes, car diac, 
re nal or h e patic diseas e). 
1 1.  S u bjects partici pati n g i n a n y cli nical trial wit h a n ot he r trial vacci ne 3 0 da ys pri or t o Da y 1 
( M 0) or i nte n di n g t o partici pate i n a n ot her cli nical trial at a n y ti me d uri n g t he c o n d uct of t his 
trial. 
1 2.  S u bjects w h o recei ve d a n y ot her v acci nes wit hi n 1 4 da ys (f or i nacti vate d v acci nes) or 2 8  d a ys 
(f or li ve vacci nes) pri or t o e nr oll me nt i n t his trial or w h o are pla n ni n g t o recei ve a n y v acci ne 
wit hi n 2 8 da ys of trial v acci ne a d mi nistrati o n.  
1 3.  S u bjects w h o ha ve use d a nti p yretics a n d/ or a n al gesic me dicati o ns wit hi n 2 4 h o urs pri or t o 
vacci nati o n. T h e reas o n f or t heir use ( pr o p h yla xis vers us treat me nt) m ust b e d oc u me nte d. Trial 
e ntr y s h o ul d be dela ye d t o all o w f or a f ull 2 4 h o urs t o ha ve passe d si nce last use of a nti p yretics 
a n d/ or a nal gesi c me dicati o ns.  
1 4.  S u bjects i n v ol ve d i n t he trial c o n d uct or t heir first -de gree relati ves.  
1 5.  S u bjects wit h a hist or y of s u bsta nce or alc o h ol a b use wit hi n t he past 2 years.  
1 6.  S u bjects w h o are pre g na nt or breastf ee di n g.  
1 7.  Fe males of c hil d beari n g p ote ntial w h o are s e x uall y acti ve a n d w h o ha ve n ot use d a n y of t he 
acce pta ble c o ntr ace pti ve met h o ds f or at l east 2 m o nt hs pri or t o Da y 1 ( M 0).  
a)  Of “c hil d beari n g p ote ntial” is defi ne d as stat us p ost -o nset of me narc he a n d n ot meeti n g 
a n y of t he f oll o wi n g c o n diti o ns: me n o pa usal f or at least 2 years, stat us after bilateral t u bal 
li gati o n f or at le ast 1 year, stat us after bilateral o o p h orect o m y, or st at us after h ysterect o m y. 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 4 3  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
b)  “ Acce pta ble birt h c o ntr ol met h o ds” are d efi ne d as o ne or m ore of t he f oll o wi n g:  
I. H or m o nal c o ntrace pti ve (s uc h as oral, i njecti o n, tra ns der mal pat c h, i m pla nt, 
cer vical ri n g).  
II. I ntr a uteri ne d e vice. 
III. M o n o ga m o us relati o ns hi p wit h vasect o mize d part ner. Part ner m ust ha v e bee n 
vasect o miz e d f or at least 6 m o nt hs pri or t o Da y 1 ( M 0).  
Ot her c o ntrace pti ve met h o ds ma y be c o nsi dere d i n a gree me nt wit h t he s p o ns or a n d will be 
a p pr o ve d b y t he a p pr o pri ate et hics c o m mittee.  
1 8.  Fe males of c hil d beari n g p ote ntial w h o are se x uall y acti ve a n d w h o ref use t o use a n acce pta ble 
c o ntrace pti ve met h o d u p t o 6 wee ks p ost -fi nal vacci nati o n o n Da y 1 8 0 ( M 6). I n a d diti o n, t he y 
m ust be a d vise d n ot t o d o nate o va d uri n g t his peri o d ( see Secti o n 9. 1. 9 ). 
1 9.  A n y p ositi ve or i n det er mi nate pre g na n c y test (see Secti o n 9. 1. 1 0 ). 
2 0.  Pre vi o us a n d pla n ne d vacci nati o n ( d uri n g t he trial c o n d uct), a gai nst a n y fla vi vir us (e x ce pt 
J a pa nese e nce p halitis [J E]) i ncl u di n g de n g ue, yell o w fe ver ( Y F) vir uses or tic k -b or ne 
e nce p h alitis.  
2 1.  Pre vi o us a n d pla n ne d va cci nati o n ( d uri n g t he trial c o n d uct) a gai nst H P V.  
2 2.  Pre vi o us partici pati o n i n a n y cli nical tri al of a d e n g ue or ot h er fla vi vir us (e g, West Nile [ W N] 
vir us) ca n di date v acci ne, e x ce pt f or s u bjects w h o recei ve d pl ace b o i n t h ose trials.  
2 3.  S u bjects wit h a c urre nt o r pre vi o us i nfecti o n wit h a fla vi vir us s uc h as Zi ka, Y F, J E, W N fe ver, 
tic k-b or ne e n ce p h alitis or M urra y Valle y e nce p halitis.  
T here ma y b e i nsta nces w he n s u bjects meet all e ntr y criteria e x ce pt o ne t hat relates t o tra nsi e nt 
cli nical circ u msta nces (e g, b o d y  te m perat ur e ele vati o n or rece nt use of e x cl u de d me dicati o n[s] or 
vacci ne[s]). U n der t hes e circ u msta nces, eli gi bilit y f or trial e nr oll me nt ma y be c o nsi dere d if t he 
a p pr o priate wi n d o w f or d ela y has p asse d, i ncl usi o n/e xcl usi o n criteria ha ve bee n rec hec ke d, a n d if 
t he s u bject is c o nfir me d t o be eli gi ble. 
7. 3  
Criteri a f or Del a y of Tri al V acci ne A d mi nistr ati o n at D a y 9 0 ( M 3) a n d D a y 1 8 0 ( M 6) 
i n Gr o u p 1, a n d D a y 1 8 0 ( M 6) i n Gr o u p 2 
After e nr oll me nt, s u bjects ma y e n c o u nter cli nical circ u msta nces t hat warra nt a dela y i n t he 
a d mi nistrati o n of trial vacci ne. T h ese sit uati o ns are liste d bel o w. I n t he e ve nt t hat a s u bject m eets a 
criteri o n f or del a y of trial vacci ne a d mi nistrati o n, t he s u bject m a y recei v e t h e trial v acci ne(s) o n ce 
t he wi n d o w f or del a y has passe d as l o n g as t he s u bject is ot her wise eli gi ble f or trial partici pati o n. 
If a n y of t he criteri a bel o w occ ur at t he ti me sc he d ule d f or t he trial vacci ne a d mi nistrati o n at 
Da y  9 0 ( M 3) a n d Da y 1 8 0 ( M 6) i n Gr o u p 1, a n d Da y 1 8 0 ( M 6) i n Gr o u p 2, t he s u bse q ue nt d ose 
ma y b e a d m i nistere d at a later date as l o n g as t he s u bject is ot her wise eli gi ble t o c o nti n ue trial 
partici pati o n. I n certai n sit uati o ns, t he peri o d of dela y ma y lea d t o de viati o n fr o m t he ti me wi n d o w 
f or t he s u bse q ue nt d os e. T he decisi o n t o vacci nate i n t h ose sit uati o ns will be ma de b y t he 
i n vesti gat or. 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 4 4  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
T he f oll o wi n g cli nical circ u msta nces w arra nt a del a y i n t he a d mi nistrati o n of trial vacci ne at 
Da y  9 0 ( M 3) a n d Da y 1 8 0 ( M 6) i n Gr o u p 1, a n d Da y 1 8 0 ( M 6) i n Gr o u p 2:  
•  S u bjects wit h a cli nicall y si g nifica nt acti ve i nfecti o n (as assesse d b y t h e i n vesti gat or) or b o d y 
te m perat ur e ≥3 8. 0° C ( ≥1 0 0. 4° F) wit hi n 3 da ys of pla n ne d trial vacci ne a d mi nistrati o n. 
•  S u bjects w h o recei ve d a n y ot her v acci nes wit hi n 1 4 da ys (f or i nacti vate d v acci nes) or 2 8  d a ys 
(f or li ve vacci nes) pri or t o pla n ne d trial vacci nati o n a d mi nistrati o n or bl o o d sa m pli n g. 
•  K n o w n or s us pect e d altere d or i m paire d i m m u ne f u ncti o n as s pecifie d u n d er t he e x cl usi o n 
criteria (s ee Secti o n 7. 2 ). 
•  S u bjects w h o ha v e us e d a nti p yretics a n d/ or a nal gesic me dicati o ns wit hi n 2 4 h o urs pri or t o trial 
vacci nati o n. T h e reas o n f or t heir use ( pr o p h yla xis vers us treat me nt) m ust b e d oc u me nte d. Trial 
vacci ne a d mi nistrati o n s h o ul d be  dela ye d t o all o w f or a f ull 2 4 h o urs t o ha v e passe d bet w ee n 
ha vi n g us e d a nti p yretics a n d/ or a nal gesi c me dicati o ns a n d trial vacci ne a d mi nistrati o n.  
7. 4  
Criteri a f or E arl y Ter mi n ati o n of a S u bject’s Tri al P arti ci p ati o n  
U n der s o me cir c u msta nces, a s u bject’s tri al p artici pati o n ma y be ter mi nat e d earl y. T his mea ns t hat 
n o f urt her trial pr oce d ures (i ncl u di n g data c ollecti o n) will be perf or m e d o n t hat s u bject be y o n d t h e 
s pecific dat e of earl y ter mi nati o n of trial partici pati o n. T he pri mar y reas o n f or earl y ter mi nati o n of 
t he s u bject’s trial partici p ati o n s h o ul d be d oc u me nte d usi n g t he f oll o wi n g cate g ories. W hile t he 
s u bject has n o o bli gati o n t o pr o vi de a reas o n f or wit h dra wi n g c o nse nt, atte m pts s h o ul d be ma de t o 
deter mi ne t he u n derl yi n g reas o n f or t he wit h dra wal a n d,  w here p ossi ble, t he pri mar y u n derl yi n g 
reas o n s h o ul d be d o c u me nte d. 
F or scree n fail ure s u bjects, refer t o Secti o n 9. 1. 1 1 . 
1.  A d verse e ve nt: t he s u bject has e x perie nc e d a n A E (irres pecti ve of bei n g rel ate d/ u nrelate d t o 
t he trial vacci n e(s), or trial-relat e d pr oce d ures) t hat re q uires earl y ter mi nati o n beca use 
c o nti n ue d partici pati o n i m p oses a n u nacce pta bl e ris k t o t he s u bject’s healt h a n d/ or t he s u bject 
is u n willi n g t o c o nti n ue p artici pati o n beca use of t h e A E. If t he s u bject is u n willi n g t o c o nti n ue 
beca use of t he A E, t he pri mar y reas o n f or earl y ter mi nati o n of trial partici pati o n i n t his case 
will be ‘ wit h dra wal d u e t o A E’ a n d n ot ‘ wit h dra wal of c o nse nt’ (see b el o w). A n y o n g oi n g A Es 
lea di n g t o earl y ter mi nati o n of trial partici pati o n s h o ul d be f oll o we d u p b y t he i n vesti gat or 
u ntil res ol uti o n or sta bilizati o n.  
2.  L ost t o f oll o w -u p: T h e s u bject di d n ot ret ur n t o t he cli nic a n d at l east 3 atte m pts t o c o ntact t h e 
s u bject were uns uccessf ul.  
3.  Wit h dra wal of c o nse nt: T he s u bject ( or s u bject’s L A R)  wis hes t o wit h dra w fr o m t he trial. T he 
pri mar y reas o n f or earl y t er mi nati o n will be “ wit h dra wal of c o nse nt” if t h e s u bject wit h dra ws 
fr o m partici pati o n d ue t o a n o n-me dical reas o n (ie, reas o n ot her t h a n a n A E). T he reas o n f or 
wit h dra wal, if pr o vi de d, s h o ul d be rec or de d i n t he e C R F.  
4.  Pre mat ure trial ter mi nati o n b y t he s p o ns or, a re g ulat or y a ge nc y, t h e I E C/I R B, or a n y ot her 
a ut h orit y.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 4 5  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
If t he cli nical trial is pr e mat urel y t er mi nate d b y t he s p o ns or, t he i n vesti gat or is t o pr o m ptl y 
i nf or m t he trial s u bjects a n d l ocal I E C/I R B a n d s h o ul d ass ure a p pr o priate f oll o w u p f or t he 
s u bjects. T he pri mar y reas o n f or earl y t er mi nati o n i n t his case will be “trial ter mi nati o n”.  
5.  S u bject’s deat h d uri n g tri al p artici pati o n.  
6.  Ot her (t he s pecific reas o n s h o ul d be rec or de d i n t he “ S pecif y” fiel d of t he e C R F).  
7. 5  
Criteri a f or Pre m at ure Disc o nti n u ati o n of Tri al V acci ne A d mi nistr ati o n  
T here are als o circ u msta nces u n der w hic h recei pt of t he trial vacci nati o n is c o ntrai n dic ate d i n t his 
trial ( Da y 9 0 [ M 3] a n d Da y 1 8 0 [ M 6] i n Gr o u p 1, or Da y 1 8 0 [ M 6] i n Gr o u p 2 o nl y).  
T hese circ u msta nces i ncl u de b ut are n ot li mite d t o a na p h yla xis or se v ere h y perse nsiti vit y reacti o ns 
f oll o wi n g t he a d mi nistrati o n of a n earlier trial vacci nati o n at Da y 1 ( M 0) a n d Da y 9 0 ( M 3) i n 
Gr o u p 1, or Da y 1 ( M 0) i n Gr o u p 2. If t hes e reacti o ns occ ur, t he s u bject m ust n ot recei ve t he tri al 
vacci nati o n at D a y 9 0 ( M 3) a n d Da y 1 8 0 ( M 6) i n Gr o u p 1, or Da y 1 8 0 ( M 6) i n Gr o u p 2, 
res pecti vel y, b ut t he s u bj ect will be e nc o ura ge d t o c o nti n ue trial partici pati o n f or safet y f oll o w -u p.  
Earl y ter mi nati o n of a s u bject’s trial partici pati o n will b y defa ult pre ve nt t h e s u bject fr o m 
recei vi n g f urt her d oses of trial vacci ne, as t he s u bj ect will n o l o n ger be partici pati n g i n t he trial.  
I n a d diti o n t o criteria f or earl y ter mi nati o n of a s u bject’s partici pati o n (s ee Secti o n 7. 4 ), ot her 
sit uati o ns ma y a p pl y i n w hic h s u bjects may c o nti n ue partici pati n g i n t he trial (e g, c o ntri b uti n g 
safet y data acc or di n g t o t he pr ot oc ol) b ut trial vacci ne a d mi nistrati o n is disc o nti n ue d.  E ve n if t he 
s u bject is dee me d i neli gi ble t o recei v e f urt her d oses of trial vacci ne, all eff orts s h o ul d be ma de  t o 
c o nti n ue t he c ollecti o n of safet y data acc or di n g t o t he pr ot oc ol.  
I n a d diti o n, t he pri mar y  reas o n f or pre mat ure disc o nti n uati o n of trial vacci ne a d mi nistrati o n 
s h o ul d be rec or de d i n t he e C R F “ E n d of Trial Vacci ne a d mi nistrati o n” pa ge usi n g t he f oll o wi n g 
cate g ories:  
1.  A d verse e ve nt: t he s u bject has e x perie nce d a n A E (irres pecti ve of bei n g rel ate d/ u nrelate d t o 
t he trial vacci n e[s] or trial-relate d pr oce d ure[s]) f or w hic h s u bse q ue nt trial vacci ne 
a d mi nistrati o ns i m p ose a n u nacce pta ble ris k t o t he s u bject’s healt h, b ut t he s u bject will 
c o nti n ue trial partici pati o n f or t he c ollecti o n of safet y d ata, or a s u bset of ot h er trial pr oce d ures.  
2.  L ost t o f oll o w -u p: t he s u bject di d n ot ret ur n t o t he cli nic a n d at least 3 atte m pts t o c o ntact t he 
s u bject were u ns uccessf ul.  
3.  Wit h dra wal of c o nse nt: t he s u bject ( or s u bject’s L A R) wis hes t o wit h dra w fr o m t he trial. T he 
pri mar y  reas o n f or earl y t er mi nati o n will be ‘ wit h dra wal of c o nse nt” if t h e s u bject wit h dra ws 
fr o m partici pati o n d ue t o a n o n-me dical reas o n (ie, reas o n ot her t h a n A E). T he reas o n f or 
wit h dra wal, if pr o vi de d, s h o ul d be rec or de d i n t he e C R F.  
4.  Pre mat ure trial ter mi nati o n b y s p o ns or, a re g ulat or y a ge nc y, t h e I E C/I R B, or a n y ot her 
a ut h orit y.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 4 6  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
If t he cli nical trial is pr e mat urel y t er mi nate d b y t he s p o ns or, t he i n vesti gat or is t o pr o m ptl y 
i nf or m t he trial s u bjects a n d l ocal I E C/I R B a n d s h o ul d ass ure a p pr o priate f oll o w-u p f or t he 
s u bjects. T he pri mar y reas o n f or earl y t er mi nati o n i n t his case will be ‘trial ter mi nati o n”.  
5.  S u bject’s deat h d uri n g tri al partici pati o n.  
6.  Pr ot oc ol de viati o n: a pr ot oc ol de viati o n is a n y c ha n ge, di v er ge n ce, or de part ure fr o m t he trial 
desi g n or pr oce d ures of a trial pr ot oc ol. T h e s u bject ma y re mai n i n t he trial u nless c o nti n uati o n 
i n t he trial je o par dizes t he s u bject’s healt h, safet y or ri g hts (s ee Secti o n 7. 4 ). 
7.  Pre g n a nc y : a n y s u bject w h o, des pite t he re q uir e me nt f or a de q u ate c o ntr ace pti o n, bec o mes 
pre g na nt d uri n g t he trial will n ot recei ve f urt her tria l vacci ne a d mi nistrati o n(s). Pre g na nt 
s u bjects s h o ul d, h o w e ver, be as ke d t o c o nti n ue partici pati n g i n t he trial c o ntri b uti n g d ata t o t he 
safet y f oll o w-u p acc or di n g t o pr ot oc ol. I n a d diti o n, t he site s h o ul d mai ntai n c o ntact wit h t he 
pre g na nt s u bject a n d c o m plete a “ Pre g na n c y F or m ” as s o o n as p ossi ble. T h e s u bject s h o ul d b e 
f oll o we d-u p u ntil t he birt h of t he c hil d, or s p o nta n e o us or v ol u ntar y ter mi n ati o n; w he n 
pre g na nc y o ut c o me i nf or mati o n bec o mes a vaila bl e, t he i nf or mati o n s h o ul d be ca pt ur e d usi n g 
t he sa me for m. Data o btai ne d fr o m t he “ Pre g n a nc y F or m” will be ca pt ure d i n t he safet y 
data base.  
8.  Ot her (t he s pecific reas o n s h o ul d be rec or de d i n t he “ S pecif y” fiel d of t he e C R F).  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 4 7  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
8. 0  
C LI NI C A L T RI A L M A T E RI A L M A N A G E M E N T  
T his secti o n c o ntai ns i nf or mati o n re gar di n g all tria l vacci n es a n d materi als pr o vi de d directl y b y 
t he s p o ns or, a n d/ or s o urce d b y ot h er mea ns, t h at are re q uir e d b y t he trial pr ot oc ol, i ncl u di n g 
i m p orta nt secti o ns descri bi n g t he ma n a ge me nt of cli nical trial materials. 
8. 1  
Tri al V acci nes a n d M ateri als  
I nvesti g ati on al v acci ne  
T D V kits ( T D V a n d T D V dil ue nt)  
T he i n vesti gati o nal vacci ne, T D V, is a De n g u e Tetra vale nt Vacci ne ( Li ve, Atte n uate d) c o m prise d 
of a  m olec ularl y c haracterize d, atte n uate d de n g u e ser ot y p e 2 strai n ( T D V-2), a de n g ue s er ot y pes 
2/ 1 rec o m bi na nt strai n  ( T D V-1), a d e n g ue s er ot y p es 2/ 3 rec o m bi na nt strai n ( T D V -3), a n d a 
de n g u e ser ot y pes 2/ 4 rec o m bi na nt strai n ( T D V -4)  wit h p ote ncies of n ot less t ha n 3. 3, 2. 7, 4. 0 a n d 
4. 5 l o g 1 0 pla q ue f or mi n g u nits per d ose of T D V -1, T D V -2, T D V -3, a n d T D V -4, res pecti vel y. T D V 
is a l y o p hiliz e d vacci ne t hat will be rec o nstit ute d i n dil ue nt ( 3 7 m M Na Cl s ol uti o n) pri or t o 
a d mi nistrati o n. Refer t o t he I B f or a d etaile d des cri pti o n.  
C o nc o mit a nt v acci ne  
9 v H P V vacci ne  
T he 9 v H P V vacci ne ( M erc k) is a rec o m bi na nt 9 -v ale nt vacci ne c o ntai ni n g t he L 1 pr otei ns f or 
H P V t y pes 6, 1 1, 1 6, 1 8, 3 1, 3 3, 4 5, 5 2, a n d 5 8. T he 9 v H P V vacci ne c o ntai ns yeast pr otei n, a n d t he 
vacci ne a nti ge n is a ds or be d o n a n al u mi n u m -c o ntai ni n g a dj u va nt. Eac h d os e of 9 v H P V vacci n e is 
0. 5 m L a n d is s u p plie d as a si n gle -d os e vial or i n prefille d s yri n ges t hat d o n ot c o ntai n late x. Refer 
t o t he prescri bi n g i nf or m ati o n of 9 v H P V vacci ne f or a detaile d descri pti o n. 
Details re gar di n g t h e d os a ge f or m d escri pti o n a n d stre n gt hs, or c o m p ositi o n f or t he 
e xte m p ora ne o us pre parati o n, of t he trial vacci ne ca n be f o u n d i n t he p har m ac y ma n ual or i n t he 
refere nce d c o m p o u n di n g ma n ual w he n a p plica ble. Trial vacci ne will be pac ka ge d t o s u p p ort 
e nr oll me nt.  
8. 1. 1  D os a ge F or m, M a n uf act uri n g, P ac k a gi n g, a n d L a beli n g  
T D V kits ( T D V a n d T D V dil ue nt)  
Ma n ufact uri n g of m o n o vale nt b ul k vacci ne s u bsta nces of T D V, mi xi n g of t he 4 T D V vacci ne 
s u bsta nces, filli n g i nt o vi als, a n d l y o p hilizati o n of T D V is d o ne at I D T Bi ol o gi ka G m b H, 
Ger ma n y.  
L y o p hiliz e d T D V is pres e nte d i n a si n gl e -d ose 2 m L glass vial wit h a gre y b ut y l r u b ber st o p per 
a n d fli p-t o p al u mi n u m o verseal. 
T D V dil ue nt ( 3 7 m M s o di u m c hl ori de s ol uti o n) is a clear, c ol orless s ol uti o n pr o vi de d i n a 
si n gle-us e 2 m L gl ass vial or a si n gle -use 1 m L glass s yri n ge a n d is use d t o rec o nstit ute t he 
l y o p hiliz e d T D V t o deliver a 0. 5 m L d ose.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 4 8  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
T he s p o ns or will s u p pl y T D V a n d T D V dil ue nt vi als/s yri n ges p ac ka ge d t o get h er i nt o si n gle d os e 
dis pe nsi n g cart o ns. T he u nits a n d cart o ns will be la bele d wit h perti ne nt trial i nf or mati o n i n l ocal 
la n g u a ges. F urt her details ca n be f o u n d i n t he P har mac y Ma n u al. 
9 v H P V vacci ne  
T he 9 v H P V vacci ne is ma n ufact ure d b y Merc k S h ar p & D o h me C or p., a s u bsi diar y of Merc k & 
C o., I nc.  
T he 9 v H P V vacci ne is pr ese nte d i n a 0. 5 m L s us p e nsi o n f or i njecti o n as a si n gle -d os e vial or as a 
prefille d s yri n ge. T he va cci ne is pre pare d fr o m t he p urifie d vir us -li ke particles of t he maj or ca psi d 
( L 1) pr otei n of H P V T y p es 6, 1 1, 1 6, 1 8, 3 1, 3 3, 4 5, 5 2, a n d 5 8. 
T he p urifie d vir us -li ke p articles are a ds or be d o n pref or me d al u mi n u m-c o nt ai ni n g a dj u v a nt: 
a m or p h o us al u mi n u m h y dr o x y p h os p h ate s ulfate.  
T he vacci ne is a sterile li q ui d s us pe nsi o n t hat is pre pare d b y c o m bi ni n g t he a ds or be d vir us -li ke 
particles of eac h H P V t y pe a n d a d diti o nal a m o u nts of t he al u mi n u m -c o ntai ni n g a dj u va nt a n d t he 
fi nal p urificati o n b uffer. 
Eac h 0. 5 m L d ose c o nt ai ns a p pr o xi matel y 3 0 µ g of H P V T y p e 6 L 1 pr otei n, 4 0 µ g of H P V T y p e 
1 1 L 1 pr otei n, 6 0 µ g of H P V T y pe 1 6 L 1 pr otei n, 4 0 µ g of H P V T y p e 1 8 L 1 pr otei n, 2 0 µ g of H P V 
T y pe 3 1 L 1 pr otei n, 2 0 µ g of H P V T y p e 3 3 L 1 pr otei n, 2 0 µ g of H P V T y pe 4 5 L 1 pr otei n, 2 0 µ g of 
H P V T y p e 5 2 L 1 pr otei n, a n d 2 0 µ g of H P V T y pe 5 8 L 1 pr ot ei n.  
Eac h 0. 5 m L d ose of t h e vacci ne als o c o ntai ns a p pr o xi matel y 5 0 0 µ g of al u mi n u m ( pr o vi de d as 
a m or p h o us al u mi n u m h y dr o x y p h os p h ate s ulfate), 9. 5 6 m g of s o di u m c hl ori de, 0. 7 8 m g of 
L -histi di ne,  5 0 µ g of p ol ys or bate 8 0, 3 5 µ g of s o di u m b orate, < 7 µ g yeast pr otei n, a n d water f or 
i njecti o n. T he pr o d uct d o es n ot c o ntai n a preser vati ve or a nti bi otics. 
After t h or o u g h a gitati o n, 9 v H P V vacci ne is a w hite, cl o u d y li q ui d.  
T he s p o ns or will s u p pl y t he trial  site wit h t he 9 v H P V vacci ne. T h e u nits a n d cart o ns will be 
la bele d wit h perti ne nt tri al i nf or mati o n i n l ocal la n g ua ges. F urt her details ca n be f o u n d i n t he 
P har mac y Ma n u al.  
8. 1. 2  St or a ge  
I nvesti g ati o n al v acci ne 
T D V a n d T D V dil ue nt will be s hi p pe d i n refri gerate d c o ntai ners at 2° C t o 8° C. Fr o m recei pt a n d 
pri or t o use, T D V a n d T D V dil ue nt m ust be pr otecte d fr o m li g ht a n d st ore d at 2° C t o 8° C i n a 
refri gerat or, b ut m ust n ot be fr oze n . 
C o nc o mit a nt v acci ne  
9 v H P V vacci ne will be s hi p pe d i n refri gerate d c o ntai ners at 2° C t o 8° C. Fr o m recei pt a n d pri or t o 
use, 9 v H P V vacci ne m ust be pr otecte d fr o m li g ht a n d st ore d at 2° C t o 8° C i n a refri gerat or, b ut 
m ust n ot be fr oze n.   
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 4 9  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
All cli nical trial materi al m ust be ke pt i n a n a p pr o priate, li mite d -access, sec ure place u ntil it is use d 
or ret ur ne d t o t he s p o ns or or desi g n ee f or destr ucti o n. All s p o ns or -s u p plie d trial vacci nes m ust be 
st ore d u n der t he c o n diti o ns s pecifie d o n t he la b el, a n d re mai n i n t he ori gi nal c o ntai ner u ntil 
dis pe nse d. A dail y te m p erat ure l o g of t he vacci ne st ora g e area m ust be mai ntai ne d e ver y w or ki n g 
da y. T e m perat ure e x c ursi o ns m ust be re p orte d t o t he s p o ns or as s o o n as p ossi ble a n d use of t hese 
vacci nes re q uires s p o ns or a p pr o val.  
8. 1. 3  D ose a n d Re gi me n  
T he trial vacci ne d oses t h at will be pr o vi de d t o eac h trial gr o u p are prese nt e d i n Ta ble  8 .a. 
T he 0. 5 m L tri al vacci ne d oses of T D V a n d 9 v P H V will be pre pare d a n d a d mi nistere d b y t he 
p har macist or vacci ne a d mi nistrat or acc or di n g t o t he i nstr ucti o ns i n t he P har mac y Ma n u al or per 
s p o ns or i nstr ucti o ns. 
T D V will be a d mi nistere d b y t he S C r o ute, a n d 9 v H P V vacci ne will be a d mi nistere d b y t he 
i ntra m usc ular (I M) r o ute. 
T a ble  8 .a  
S p o ns or -S u p plie d Tri al V acci nes  
Gr o u p  
N u m ber of s u bjects  
D a y 1 ( M 0) 
D a y 9 0 ( M 3)  
D a y 1 8 0 ( M 6)  
Gr o u p 1  
3 0 7  
T D V + 9 v H P V  
T D V  
9 v H P V  
Gr o u p 2  
3 0 7  
9 v H P V  
 
9 v H P V  
N ote: c o -a d mi nistere d trial va cci nes will be i nj ecte d i n o p p osite ar ms.  
9 v H P V = Rec o m bi na nt 9 -vale nt h u ma n pa pill o ma vir us vacci ne, M = m o nt h, T D V = De n g ue T etra vale nt Vacci ne ( Li ve, 
Atte n uate d).  
8. 2  
Tri al V acci ne Assi g n me nt a n d Dis pe nsi n g Pr oce d ures  
Trial vacci nes will be i de ntifia ble b y a u ni q ue i de ntificati o n n u m ber a n d ma na ge d b y I nteracti ve 
Res p o nse Tec h n ol o g y (I R T). Refer t o Secti o n 8. 6  f or acc o u nta bilit y of s p o ns or-s u p plie d vacci nes. 
T he i n vesti gat or or desi g nee will use I R T at s u bject e nr oll me nt t o o btai n t he s u bject n u m ber (s ee 
Secti o n  9. 1. 1 ). T his n u m ber will be use d t hr o u g h o ut t he trial. 
T he i n vesti gat or or desi g nee will use I R T at eac h dis pe nsi n g visit t o o btai n t he vacci n ati o n 
i de ntificati o n n u m ber f or t he vacci n e d ose. 
T he i n vesti gat or or desi g nee will be res p o nsi ble f or o verseei n g t he a d mi nistrati o n of vacci ne(s) t o 
s u bjects e nr olle d i n t he trial acc or di n g t o t he pr oce d ures sti p ulate d i n t his trial pr ot oc ol. T he 
vacci ne will be a d mi nistere d o nl y b y pers o n nel w h o are q ualifi e d t o perf or m t hat f u ncti o n u n der 
a p plica ble la ws a n d re g ul ati o ns f or t hat s pecific trial.  
If s p o ns or-s u p plie d trial vacci ne is l ost or da ma ge d, t he site ca n re q uest a re place m e nt. E x pire d 
trial vacci nes m ust n ot be a d mi nistere d. 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 5 0  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
8. 2. 1  Prec a uti o ns t o be O bser ve d  W he n A d mi nisteri n g t he Tri al V acci ne(s)  
Pri or t o trial vacci ne a d mi nistrati o n, a s u bject m ust be deter mi ne d t o be eli gi ble t o recei ve tri al 
vacci ne(s) a n d it m ust be cli nicall y a p pr o priate i n t he j u d g me nt of t he i n v esti gat or t o a d mi nister 
t he trial vacci ne(s).  
First, trial eli gi bilit y is e v al uate d acc or di n g t o t he e ntr y criteri a o utli ne d i n t his pr ot oc ol 
( Secti o ns 7. 1  a n d 7. 2 ). O nce eli gi bilit y is c o nfir m e d, t he s u bject will recei ve t he first trial 
vacci nati o n(s) ( Da y 1 [ M 0]) acc or di n g t o ra n d o m trial gr o u p all ocati o n .  
Pri or t o s u bse q ue nt tria l vacci ne a d mi nistrati o n ( o n Da y 9 0 [ M 3] f or Gr o u p 1, a n d o n Da y 1 8 0 
[ M 6] f or Gr o u p 1 a n d 2), site staff m ust deter mi ne if t he s u bject is eli gi ble t o recei v e vacci nati o n 
b y e v al uati n g t he criteria o utli ne d i n Secti o ns 7. 3 , 7. 4  a n d 7. 5 . 
Trial vacci ne(s) s h o ul d n ot be a d mi nistere d t o i n di vi d uals wit h k n o w n h y perse nsiti vit y t o a n y 
c o m p o ne nt of t he vacci n e(s).  
Sta n dar d i m m u niz ati o n practices are t o b e o bser ve d a n d care s h o ul d be ta ke n t o a d mi nister t he 
i njecti o n b y t he S C ( T D V) or I M ( 9 v H P V) r o ute. I n a d diti o n, W H O rec o m me n dati o ns t o re d uce 
a n xiet y a n d pai n at t he ti me of vacci nati o n s h o ul d be f oll o we d [ 2 3 ]. Bef ore a d mi nisteri n g t he trial 
vacci n e(s), t he vacci nati o n site(s) m ust be disi nfecte d wit h a s ki n disi nfecta nt (e g, 7 0 %  alc o h ol). 
All o w t he s ki n t o dr y. I n Gr o u p 1 o n Da y 1 ( M 0), c o nc o mita nt vacci n e a d mi nistrati o n ( T D V a n d 
9 v H P V) vacci ne will be i njecte d i n o p p osite ar ms. Refer t o t he p har ma c y m a n ual f or d etails o n 
pre parati o n a n d a d mi nistrati o n of trial vacci nati o n.  
After eac h tri al vacci nati o n ( T D V a n d/ or 9 v H P V v acci ne), t he s u bject will be o bser ve d f or at least 
3 0 mi n utes f or se vere reacti o ns. As wit h all i njecta ble vacci n es, trai ne d me dic al pers o n nel a n d 
a p pr o priate m e dical treat me nt s h o ul d be rea dil y a vaila ble i n case of a na p h yl actic reacti o ns 
f oll o wi n g vacci nati o n. F or e x a m ple, e pi ne p hri ne 1: 1 0 0 0, di p he n h y dra mi ne, a n d/ or ot her 
me dicati o ns f or treati n g a na p h yla xis s h o ul d be a vaila ble. T he se resc u e me dicati o ns will n ot be 
s u p plie d b y t he s p o ns or. 
8. 3  
R a n d o miz ati o n C o de Cre ati o n a n d St or a ge  
Ra n d o mizati o n pers o n nel of t he s p o ns or or desi g n ee will ge nerate t he ra n d o mizati o n sc he d ule. 
Ra n d o mizati o n i nf or mati o n will be st ore d i n a sec ure d area, accessi ble o nl y b y a ut h orize d 
pers o n nel.  
8. 4  
Tri al V acci ne Bli n d M ai nte n a nce  
T o pre ve nt bias or t h e perce pti o n of bias, st u d y tea m me m bers res p o nsi ble f or decisi o n ma ki n g 
re gar di n g st u d y c o n d u ct or a nal ysis of data after t he first s u bject e nr oll me nt (e g pr ot ocol 
a me n d me nt a n d S A P a m e n d me nt) will be d oc u me nte d i n t he data access m a na ge me nt pla n, a n d 
will be i n de pe n de nt of u n bli n de d data re vie w.  
8. 5  
U n bli n di n g Pr oce d ure  
N ot a p plica ble.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 5 1  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
8. 6  
Acc o u nt a bilit y a n d Destr ucti o n of S p o ns or -S u p plie d Tri al V acci ne  
Vacci n e s u p plies will be c o u nte d a n d rec o ncile d at t he site bef ore b ei n g l o call y destr o ye d or 
ret ur ne d t o t he s p o ns or or desi g n ee as n ote d bel o w. T he sites will mai ntai n s o urce d oc u m e nts i n 
a d diti o n t o e nteri n g d ata i n I R T.  Ot her a ncillar y cli nical trial materials will n ot  be ret ur ne d t o t he 
s p o ns or. 
T he i n vesti gat or or desi g nee m ust e ns ure t hat t he s p o ns or -s u p plie d trial vacci ne(s) (T D V 
i ncl u di n g T D V dil ue nt, 9 v H P V vacci ne) are use d i n acc or da nce wit h t he a p pr o ve d pr ot oc ol a n d 
is/are a d mi nistere d o nl y t o s u bjects e nr olle d i n t he trial. T o d oc u me nt a p pr o priate use of 
s p o ns or-s u p plie d trial vacci ne(s) (T D V i ncl u di n g T D V dil ue nt, 9 v H P V vacci ne) , t he i n vesti gat or 
m ust mai ntai n rec or ds of all s p o ns or -s u p plie d trial vacci ne(s) deli ver y t o t he site, site i n ve nt or y, 
a d mi nistrati o n a n d use b y eac h s u bject, a n d destr ucti o n or ret ur n t o t he s p o ns or or desi g nee.  
U p o n recei pt of s p o ns or -s u p plie d trial vacci ne(s), t he i n vesti gat or or desi g n ee m ust verif y t he 
c o nte nts of t he s hi p me nts a gai nst t he pac ki n g list. T he verifier s h o ul d e ns ure t h at t he q ua ntit y is 
c orrect, t he trial va cci nes are recei ve d wit hi n t he la bele d st ora ge c o n diti o ns (ie, n o c ol d c hai n 
brea k has o cc urre d d uri n g tra nsit), a n d are i n g o o d c o n diti o n. If q ua ntit y a n d c o n diti o ns are 
acce pta ble, i n vesti gat or or desi g n ee will ac k n o wle d ge recei pt of t he s hi p me nt b y rec or di n g i n I R T.  
If t here are a n y discre pa n cies bet wee n t he pac ki n g list vers us t he act ual pr o d uct recei ve d, t he 
s p o ns or or desi g nee m ust be c o ntact e d t o res ol ve t he iss ue. T he pac ki n g list s h o ul d be file d i n t he 
P har ma c y I n v esti gat or Site File b y a q u alifie d i n vesti gat or d esi g n ee.  
T he i n vesti gat or ( or desi g nat e d i n di vi d ual) m ust mai ntai n 1 0 0 %  acc o u nt a bilit y f or all 
s p o ns or-s u p plie d trial vacci nes ( T D V i ncl u di n g T D V dil ue nt, 9 v H P V vacci ne) recei ve d a n d 
a d mi nistere d d uri n g t heir e ntire partici pati o n i n t he trial. Acc o u nta bilit y i ncl u des, b ut is n ot li mite d 
t o: 
•  Verif yi n g t hat act ual i n ve nt or y m atc hes d o c u me nte d i n ve nt or y.  
•  Verif yi n g t hat t he l o g is c o m plete d f or t he v acci n e l ot n u m ber use d t o pre p are eac h d os e.  
•  Verif yi n g t ha t all trial va cci ne kits use d are d oc u me nte d acc uratel y o n t he l o g. 
•  Verif yi n g t hat re q uire d fi el ds are c o m plete d acc uratel y a n d le gi bl y.  
If a n y dis pe nsi n g err ors or discre pa nci es are disc o v ere d, t he s p o ns or m ust be n otifie d i m me diatel y. 
T he p har macist ( or desi g nate d i n di vi d ual) at t he site m ust rec or d t he c urre nt i n ve nt or y of all 
s p o ns or-s u p plie d vacci n es (T D V i ncl u di n g T D V dil ue nt, 9 v H P V vacci ne ) o n a s p o ns or-a p pr o ve d 
trial vacci ne acc o u nta bilit y l o g. T he f oll o wi n g i nf or mati o n will be rec or de d as a mi ni m u m: 
pr ot oc ol n u m ber a n d title, na me of i n vesti gat or, sit e i de ntifier a n d n u m b er, descri pti o n of 
s p o ns or-s u p plie d trial vacci nes, e x pir y a n d/ or retest date, a n d a m o u nt. T he l o g s h o ul d i ncl u de all 
re q uire d i nf or mati o n as a se parat e e ntr y f or eac h s u bject t o w ho m s p o ns or -s u p plie d trial vacci ne(s) 
is a d mi nistere d. 
T he i n vesti gat or will be n otifie d of a n y e x pir y d ate or ret est date e xte nsi o n of trial vacci ne(s) or 
cli nical trial material d uri n g t he trial c o n d uct. O n e x pir y date n otificati o n fr o m t he s p o ns or, t he s ite 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 5 2  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
m ust c o m plete all i nstr ucti o ns o utli ne d i n t he n otificati o n, i ncl u di n g se gre gati o n of e x pire d cli nical 
trial material f or ret ur n t o t he s p o ns or or its desi g n ee f or d estr ucti o n. 
Pri or t o site cl os ure or at a p pr o priate i nter vals t hr o u g h o ut t he trial, bef ore a n y trial vacci ne(s) are 
destr o ye d l ocall y  or cli ni cal trial materials are ret ur ne d t o t he s p o ns or or desi g nee f or destr u cti o n, 
a re prese ntati ve fr o m t he s p o ns or or its desi g n ee will perf or m cli nical trial material acc o u nta bilit y 
a n d rec o nciliati o n. T h e i n vesti gat or will retai n a c o p y of t he d oc u me ntati o n re gar di n g cli nical trial 
material acc o u nta bilit y, ret ur n a n d/ or destr u cti o n, a n d ori gi n als will be se nt t o t he s p o ns or or 
desi g nee.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 5 3  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
9. 0  
T RI A L P L A N  
9. 1  
Tri al Pr o ce d ures  
T he f oll o wi n g s ecti o ns d escri be t he tri al  pr oce d ures a n d data t o be c ollecte d. F or eac h pr oce d ure, 
s u bjects are t o be assesse d b y t he s a me i n vesti gat or or site pers o n nel w he ne ver p ossi ble. All 
pr oce d ures m ust be perf or me d b y q ualifie d a n d tr ai ne d staff.  
T he Sc he d ule of Trial Pr oce d ures is l ocate d i n Secti o n 2. 1 . 
9. 1. 1  I nf or me d C o nse nt a n d Pe di at ric Asse nt F o r m 
T he re q uire me nts of t he i nf or me d c o nse nt a n d pe diatric asse nt f or m are des cri be d i n Sec ti o n 1 5. 2 . 
I nf or me d c o ns e nt or pe di atric asse nt m ust be o btai ne d pri or t o t he s u bject e nteri n g i nt o t he trial, 
a n d bef ore a n y pr ot oc ol -directe d pr oce d ures are p erf or me d.  
A u ni q ue s u bject n u m ber will be assi g ne d t o eac h s u bject b y t he I R T after i nf or me d c o ns e nt or 
pe diatric asse nt is o btai n e d. If all eli gi bilit y criteri a are f ulfille d, t his s u bject n u m ber will be use d 
t hr o u g h o ut t he trial. S u bj ect n u m bers assi g ne d t o s u bjects w h o fail scree ni n g ass ess me nts o n 
Da y  1 ( M 0) s h o ul d n ot b e re use d (see Secti o n 9. 1. 1 1 ). 
9. 1. 2  De m o gr a p hics, Me dic al Hist or y a n d Pri or Me dic at i o ns 
De m o gra p hic i nf or mati o n t o be o btai ne d o n Da y 1 ( M 0) will i ncl u de a ge/ d ate of birt h, se x, race, 
a n d et h nicit y as descri be d b y t he s u bject or s u bject’s L A R . 
Me dical hist or y will be c ollecte d ( Da y 1 [ M 0]), i ncl u di n g b ut n ot li mite d t o a n y m e dical hist ory 
t hat ma y b e rele v a nt t o s u bject eli gi bilit y f or trial partici pati o n s uc h as pri or 
me dicati o ns/ vacci nati o ns a n d pre vi o us a n d o n g oi n g ill nesses a n d/ or i nj uries. Use of c o n c o mita nt 
me dicati o ns/ vacci nati o ns will be c ollecte d t hr o u g h o ut t he trial u ntil Da y 3 6 0 ( M 1 2) . Rele va nt 
me dical hist or y ca n als o i ncl u de a n y me dical hist or y t hat c o ntri b utes t o t he u n dersta n di n g of a n A E 
t hat occ urs d uri n g trial p artici pati o n, if it re pres e nts a n e x acer bati o n of a n u n derl yi n g 
disease/ pree xisti n g pr o ble m.  
Me dical hist or y (i n cl u di n g c orres p o n di n g me dicati o n) t o be o btai ne d will i ncl u de a n y si g nifica nt 
c o n diti o ns or diseases t hat ha ve disa p peare d or res ol ve d at or pri or t o si g ni n g of i nf or me d c o nse nt 
or pe diatric asse nt f or m . 
A d verse me di cal oc c urre nces e mer gi n g d uri n g t h e ti me  be t wee n si g ni n g of i nf or me d c o nse nt or 
pe diatric asse nt f or m a n d t he first a d mi nistrati o n of trial vacci ne will be rec or de d i n t he “ Me di cal 
H ist or y” C R F p a ge. If s u c h a n a d v erse me di cal occ urre n ce is assess e d as relate d t o a trial 
pr oce d ure t his s h o ul d be  rec or de d i n t he e C R F as a n A E rel ate d t o trial pr oce d ure.  
All me dicati o ns, vacci nes a n d bl o o d pr o d ucts ta ke n or recei v e d b y t h e s u bj ects are t o b e c ollecte d 
as “ Pri or a n d C o nc o mita nt Me dicati o ns” a n d rec or de d o n t he “ Pri or a n d C o nc o mita nt 
Me dicati o ns” e C R F a n d i n t he s u bject’s s o urce d o c u me nt : 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 5 4  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
•  Me dicati o ns: fr o m 1 m o nt h ( mi ni m u m 2 8 da ys) pri or t o a d mi nistrati o n of eac h trial vacci ne 
d ose u p t o 1 m o nt h ( mi ni m u m 2 8 da ys) t hereafter.  
•  Vacci n es: fr o m 1 m o nt h ( mi ni m u m 2 8 da ys) pri or t o a d mi nistrati o n of eac h tria l vacci ne d os e 
u p t o 1 m o nt h ( mi ni m u m 2 8 da ys) t hereafter.  
•  Ster oi ds a n d i m m u n osti m ula nts wit hi n 6 0 da ys pri or t o Da y 1 ( M 0).  
•  I m m u n o gl o b uli ns a n d bl o o d pr o d ucts wit hi n 3 m o nt hs pri or t o Da y 1 ( M 0). 
•  I m m u n os u p pr essi ve t hera p y wit hi n 6 m o nt hs pri or t o Da y 1 ( M0).  
T he use of a nti p yretics a n d/ or a nal gesic me di cati o ns wit hi n 2 4 h o urs pri or t o vacci nati o n m ust be 
i de ntifie d a n d t he reas o n f or t heir use ( pr o p h yla xis vers us treat me nt) m ust b e descri b e d i n t he 
s o urce d oc u m e nts or t he e C R F. Trial vacci nati o n s h o ul d be dela ye d if s u bj ects ha ve us e d 
a nti p yretics a n d/ or a n al gesic me dicati o ns wit hi n 2 4 h o urs pri or t o vacci ne a d mi nistrati o n (see 
Secti o n 7. 3 ). 
Me dicati o ns ta ke n f or pr o p h yla xis are t h ose i nte n de d t o pre ve nt t he o ns et of A Es f oll o wi n g trial 
vacci nati o n(s). Me di cati o ns ta ke n f or treat me nt are i nte n de d t o re d uce or eli mi nate t he pres e nce of 
s y m pt o ms t hat are prese nt. 
Pr o hi bite d t hera pies (see als o Secti o n 7. 2 ): 
•  Pare nteral i m m u n o gl o b uli n pre parati o n, bl o o d pr o d ucts, a n d/ or bl o o d -deri v e d pr o d ucts wit hi n 
3 m o nt hs pri or t o Da y 1 ( M 0).  
•  I m m u n os u p pr essi ve t hera p y wit hi n 6 m o nt hs or s yste mic (e g, oral or pare nteral) c ortic oster oi d 
treat me nt wit hi n 6 0 da ys pri or t o Da y 1 ( M 0) or i m m u n osti m ula nts wit hi n 6 0 da ys pri or t o 
Da y  1 ( M 0).  
•  A n y ot her vacci nes wit hi n 1 4 da ys (f or i nacti vate d vacci nes) or 2 8 da ys (f or li ve vacci nes) 
pri or t o Da y 1 ( M 0) a n d Da y 9 0 ( M 3), a n d 2 8 da ys after eac h tri al vacci n ati o n.  
•  Use of a nti p yretics a n d/ or a nal gesic m e dicati o ns wit hi n 2 4 h o urs pri or t o trial vacci n e 
a d mi nistrati o n at Da y 1 ( M 0), or Da y 9 0 ( M 3) a n d Da y 1 8 0 ( M 6). Trial v acci ne a d mi nistrati o n 
s h o ul d be dela ye d t o all o w f or a f ull 2 4 h o urs t o ha ve passe d si n ce last use of a nti p yretics 
a n d/ or a nal gesi c me dicati o ns.  
•  A n y ot her de n g u e vacci nes (i n vesti gati o nal o r lice nse d) f or t he e ntire trial p eri o d. 
•  Recei pt of a n y ot her cli nical trial pr o d uct wit hi n 3 0 da ys pri or t o Da y 1 ( M 0).  
T hese data m ust be writte n i n t he s u bject’s s o urce d oc u me nts.  
9. 1. 3  D oc u me nt ati o n of Tri al E ntr a nce/ R a n d o miz ati o n  
O nl y s u bjects w h o ha v e a si g ne d a pe di atric ass e nt f or m a n d i nf or me d c o ns e nt f or m, meet all of t he 
i ncl usi o n criteria a n d n o n e of t he e x cl usi o n criteria are eli gi ble f or ra n d o mizati o n i nt o t his trial. 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 5 5  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
T he ra n d o mizati o n sc he d ule will be create d a n d c o ntr olle d b y t he I R T pr o vi der. T he  
ra n d o mizati o n s pecificati o n will be a p pr o ve d b y t he s p o ns or’s trial statisticia n, or desi g nee. 
If t he s u bject is i neli gi ble f or ra n d o mizati o n, t he i n vesti gat or s h o ul d rec or d t he pri mar y reas o n f or 
fail ure o n t he s u bject e nr oll me nt l o g. 
9. 1. 4  P h ysic al E x a mi n ati o n  
P h ysical e x a mi nati o ns m ust be perf or m e d b y a q u alifie d healt h pr ofessi o nal i n acc or da n ce wit h 
l ocal re g ulati o ns a n d as liste d wit hi n t he Site Res p o nsi bilit y Del e gati o n L o g.  
A c o m plete p h ysical e x a mi nati o n will be perf or m e d o n Da y 1 ( M 0), Da y 9 0 ( M 3) a n d  Da y 1 8 0 
( M 6) acc or di n g t o t he i n vesti gat or’s sta n dar d practice. A c o m plete p h ysi cal e xa mi nati o n i ncl u des 
b ut is n ot li mite d t o: a usc ultati o n of heart a n d l u n gs, pal pati o n of t he a b d o m e n, i ns pecti o n of 
e xtre mities (i ncl u di n g s ki n o ver i nte n de d vacci nati o n site[s]), a c hec k of ge neral a p peara nce a n d 
t he meas ure m e nt of wei g ht a n d hei g ht; b o d y mass i n de x will be calc ulate d  a ut o maticall y.  
A d diti o nal p h ysical e x a mi nati o ns ma y be perf or me d if i n dicate d b y re vie w of t he s u bject’s 
me dical hist or y. T h e fi n di n gs s h o ul d be d oc u me nt e d i n t he s u bject’s s o urce d oc u me nt. 
Tar gete d p h ysic al e x a mi nati o n will be perf or me d o n Da y 3 0 ( M 1), Da y 1 2 0 ( M 4), Da y 2 1 0 ( M 7), 
a n d Da y 3 6 0 ( M 1 2 ) a n d i ncl u des b ut n ot li mite d t o t he meas ure m e nt of vital si g ns (see 
Secti o n  9. 1. 5 ). Si g nifica nt cli nical differe nces fr o m t he baseli ne assess me nt m ust be rec or de d i n 
t he s u bject’s s o urce d oc u me nts a n d t he “a d v erse e ve nt” e C R F. 
S y m pt o m -dir ecte d p h ysi cal e x a mi nati o n ma y be perf or me d if dee m e d necessar y.  
9. 1. 5  Vit al Si g ns  
Vital si g ns will be rec or de d o n Da y 1 ( M 0), Da y 3 0 ( M 1), Da y 9 0 ( M 3), Da y 1 2 0 ( M 4), Da y 1 8 0 
( M 6), Da y 2 1 0 ( M 7), a n d Da y 3 6 0 ( M 1 2). T h ese will i ncl u de ( b ut are n ot li mite d t o) t he 
meas ure me nt of s yst olic bl o o d press ure/ diast olic bl o o d press ure, h eart rate, a n d b o d y t e m perat ure.   
9. 1. 6  I m m u n o ge nicit y Ass ess me nts 
Bl o o d sa m ples f or t he m eas ure m e nt of H P V ne utr alizi n g a nti b o dies ( Merc k assa y) f or b ot h 
Gr o u ps 1 a n d 2 will be c ollecte d at pre -first va cci nati on ( Da y 1 [ M 0]) a n d at 1 m o nt h (at least 
2 9  da ys) p ost -sec o n d 9 v H P V vacci nati o n ( Da y 2 1 0 [ M 7]). 
Bl o o d sa m ples f or t he m eas ure m e nt of de n g ue n e utralizi n g a nti b o dies ( b y M N T 5 0) will be 
c ollecte d f or Gr o u p 1 o nl y at pr e -first vacci n ati o n ( Da y 1 [ M 0]) a n d at 1 m o nt h (at least 2 9 da ys) 
p ost -sec o n d T D V v acci n ati o n ( Da y 1 2 0 [ M 4]).  
All sa m ples will be c ollecte d i n acc or da n ce wit h acce pta bl e la b orat or y pr oce d ures. Bl o o d sa m ples 
will be pr ocesse d a n d st ore d at t he trial site acc or di n g t o t he La b orat or y G ui deli nes as pr o vi de d i n 
t he La b orat or y M a n ual.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 5 6  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
9. 1. 7  Pr o cessi n g, L a beli n g a n d St or a ge of Bi ol o gic al S a m ples  
All bl o o d sa m ples will be pr ocess e d, la bele d a n d st ore d acc or di n g t o t he La b orat or y Ma n ual or 
ot her a p pr o pri ate g ui deli ne pr o vi de d t o t he site.  
9. 1. 8  S afet y Assess me nts  
Sa fet y assess m e nts will i ncl u de c ollecti o n a n d rec or di n g of s olicite d l o cal (i njecti o n site) reacti o ns 
a n d s olicite d s yste mic A Es, u ns olicite d A Es (seri o us a n d n o n-seri o us), a n d pre g na nci es.  
Refer t o Secti o n 1 0. 1  f or safet y defi niti o ns. Details o n c ollecti o n a n d re p orti n g of A Es are i n 
Secti o n 1 0. 4 . 
9. 1. 9  C o ntr ace pt i o n a n d Pre g n a nc y A v oi d a nce Pr o ce d ure 
F or fe male s u bjects of c hil d beari n g p ot e ntial, uri ne pre g na n c y testi n g will be perf or me d pri or t o 
eac h trial d ose a d mi nistrati o n (f or b ot h Gr o u ps 1 a n d 2 o n Da y 1 [ M 0] a n d Da y 1 8 0 [ M 6], a n d f or 
Gr o u p 1 o nl y o n Da y 9 0 [ M 3]).  
Fe male s u bjects will be pr o vi de d wit h i nf or mati o n o n acce pta ble m et h o ds of c o ntrace pti o n as p art 
of t he s u bject i nf or me d c o nse nt pr ocess a n d will be as ke d t o si g n a c o ns e nt f or m stati n g t hat t he y 
u n dersta n d t he re q uire me nts f or a v oi da nce of pre g na nc y a n d d o nati o n of o v a. S u bjects will recei ve 
c o nti n ue d g ui da nce wit h res pect t o t he a v oi da nce of pre g n a nc y as p art of t h e trial pr oce d ures, a n d 
fe males of c hil d beari n g p ote ntial w h o are s e x uall y acti ve will be re mi n de d d uri n g trial visits t o 
a d here t o acce pta ble c o ntrace pti ve m et h o ds (as defi ne d i n e xcl usi o n criteri o n n u m ber 1 7 b) u p t o 
6  wee ks after t he last d os e of T D V ( Da y  9 0  [ M 3] +  6 wee ks) or 6 wee ks after t he last d ose of 
9 v H P V ( Da y  1 8 0 [ M 6]  +  6  wee ks). T h e i n vesti gat or or desi g nee s h o ul d e x pla i n perti ne nt as pects 
of t he trial i n a n a ge a p pr o priate ma n ner t o pe di atric s u bjects i n acc or da nce wit h l ocal re g ul ati o ns.  
Refer als o t o Secti o ns 2. 1  a n d 7. 2 . 
9. 1. 1 0  Pre g n a nc y  
T o e ns ure fe male s u bject safet y a n d t he s afet y of t he u n b or n c hil d, eac h pre g na n c y i n a s u bject 
ha vi n g recei ve d a trial v acci n e m ust be re p orte d t o t he s p o ns or wit hi n 2 4 h o urs of t he site lear ni n g 
of its occ urre nce. If a s u bject bec o mes pre g na nt d uri n g t he tri al, s he will n ot recei v e a n y f urt her 
d oses of a n y trial va cci ne. T he pre g n a nc y m ust be f oll o we d t o deter mi ne o utc o me, i ncl u di n g 
s p o nta ne o us or v ol u ntar y ter mi nati o n, details of birt h, a n d t he pres e nce or a bse nce of a n y birt h 
defects, c o n ge nital a b n or malities, or mater nal a n d/ or ne w b or n c o m plicati o ns. T his f oll o w -u p 
s h o ul d occ ur e v e n if t he i nte n de d d urati o n of safet y f oll o w-u p f or t he trial h as e n de d.  
A n y pre g na n c y occ urri n g f oll o wi n g trial vacci ne a d mi nistrati o n s h o ul d be re p orte d i m me diatel y, 
usi n g a “ Pre g na n c y f or m ”, t o t he c o ntact liste d i n t he I n v esti gat or Site File.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 5 7  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
9. 1. 1 1  D oc u me nt ati o n of S u bjects W h o Are N ot R a n d o mize d  
I n v esti gat ors m ust acc o u nt f or all s u bjects w h o si g n a n i nf or me d c o ns e nt or w h o ha ve a si g n e d 
pe diatric asse nt f or m . If t he s u bject is f o u n d t o be n ot eli gi ble at t his visit ( Da y 1 [ M 0]), t he 
i n vesti gat or s h o ul d c o m plete t he e C R F acc or di n gl y. 
T he pri mar y reas o n f or n o n-ra n d o mizati o n is rec or de d i n t h e e C R F usi n g t h e f oll o wi n g cate g ori es: 
•  A d verse me di cal oc c urre nce pri or t o r ecei pt of i n v esti gati o nal vacci ne(s).  
•  Scree n fail ure ( di d n ot m eet o ne or m or e i ncl usi o n criteria or di d meet o ne or m ore e x cl usi o n 
criteria)  
•  Wit h dra wal b y s u bject  
•  Trial ter mi nate d b y t he s p o ns or  
•  Site ter mi nate d b y s p o ns or.  
•  Ot her (s pecif y reas o n)  
S u bject n u m bers assi g n e d t o s u bjects w h o fail eli gi bilit y pr oce d ures o n Da y 1 ( M 0) s h o ul d n ot be 
re-use d . 
9. 2  
M o nit ori n g S u bject C o m pli a nce  
T he i n vesti gat or or desi g nee rec or ds all a d mi nistrate d i njecti o ns of trial vacci nes ( T D V, 9 v H P V 
vacci ne) gi ve n t o t he s u bject i n t he s u bject’s s o urce d oc u me nt a n d t he e C R F . 
9. 3  
Sc he d ule of O bser v ati o ns a n d Pr oce d ures  
T he sc he d ule f or all trial -relate d pr oce d ures f or all e val uati o ns is s h o w n i n Ta ble 2 .a i n 
Secti o n  2. 1 . Assess me nts s h o ul d be c o m plete d at t he desi g n ate d visit(s)/ti me p oi nt(s). Visit 
wi n d o ws will be c o u nte d fr o m t he da y of vacci n ati o n ( Da y 1, Da y 9 0 a n d Da y 1 8 0 f or Gr o u p 1; 
Da y 1 a n d Da y  1 8 0 f or Gr o u p 2) wit h at le ast  2 9 da ys b ef ore t he ne xt sc he d ule d cli nic visit.  
9. 3. 1  Pre -V a cci n ati o n Pr oce d ures ( D a y 1 [ M 0], D a y 9 0 [ M 3] a n d D a y 1 8 0 [ M 6])  
Pre -vacci nati o n pr oce d ures will be perf or me d f or all s u bjects ( Gr o u p 1 a n d 2) o n Da y 1 ( M 0). 
U nless ot her wise s tate d t hese pr oce d ures will be re peate d o n Da y 9 0 ( M 3) f or Gr o u p 1 o nl y, a n d 
o n Da y 1 8 0 ( M 6) f or Gr o u p 1 a n d 2. 
1.  Bef ore perf or mi n g a n y trial pr oce d ure, t he si g ne d i nf or me d c o nse nt f or m  a n d pe diatric asse nt 
f or m nee ds t o be o btai n e d ( Da y 1 [ M 0]). Refer t o Se cti o n 9. 1. 1 . 
2.  C hec k i ncl usi o n a n d e x cl usi o n criteria ( Da y 1 [ M 0]). Refer t o Secti o n 7. 1  a n d Secti o n  7. 2 , 
res pecti vel y. 
3.  C ollect de m o gra p hic dat a, me dical hist or y, a n d pri or me dicati o n/ vacci n ati o n ( Da y  1  [ M 0]). 
Refer t o Secti o n 9. 1. 2 . 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
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Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
4.  C ollect c o nc o mita nt me dicati o ns/ vacci nati o ns dat a. Refer t o Secti o n 9. 1. 2 . 
5.  Re vie w of s yste ms: re vie w of s yst e ms is a str uct ur e d i nter vie w t hat q ueries t he s u bject as t o 
a n y c o m plai nts t he s u bje ct has e x perie nce d acr oss eac h or ga n s yste m.  
6.  Perf or m a c o m plet e p h ysical e x a mi nati o n ( Da y 1 [ M 0]). Refer t o Secti o n 9. 1. 4 . 
7.  C hec k vital si g ns ( Da y 1 [ M 0]). Refer t o Secti o n 9. 1. 5 . 
8.  Perf or m pre g n a nc y testi n g ( uri ne) f or fe mal es of c hil d beari n g p ot e ntial o n Da y 1 [ M 0], Da y 9 0 
[ M 3] a n d Da y 1 8 0 [ M 6] i n Gr o u p 1, a n d o n Da y 1 [ M 0], Da y 1 8 0 [ M 6] i n Gr o u p 2. Refer t o 
Secti o n  9. 1. 1 0 . 
9.  Pr o vi de g ui da n ce wit h r es pect t o t he a v oi da nce of pre g na nc y f or fe males of c hil d beari n g 
p ote ntial w h o are s e x uall y acti ve  wit h me n . Refer t o Secti o n 9. 1. 9 . 
1 0.  Ra n d o mize t he s u bject ( Da y 1 [ M 0]).  
1 1.  C ollect a bl o o d sa m ple pri or t o vacci n ati o n o n Da y 1 ( M 0) fr o m s u bjects i n Gr o u p 1 a n d  2 . 
Refer t o Secti o ns 9. 1. 6 . 
Bl o o d s h o ul d be ta ke n fr o m t he s u bject usi n g a n ase ptic ve ni p u nct ure t ec h ni q ue f or ser ol o gical 
i m m u n o ge nicit y testi n g. 
9. 3. 2  V acci n ati o n Pr oce d ures ( D a y 1 [ M 0], D a y 9 0 [ M 3] a n d D a y 1 8 0 [ M 6])  
Vacci n ati o n pr oce d ures will be perf or me d f or all s u bjects ( Gr o u p 1 a n d 2) o n Da y 1 ( M 0), u nless 
ot her wise state d t hes e pr oce d ures will be re peate d o n Da y 9 0 ( M 3) f or Gr o u p 1 o nl y, a n d o n Da y 
1 8 0 ( M 6) f or Gr o u p 1 a n d 2. 
1.  C hec k criteri a f or d ela y of trial vacci nati o n (f or Gr o u p 1 o n Da y 9 0 [ M 3] a n d Da y 1 8 0 [ M 6], 
a n d f or Gr o u p 2 o nl y o n Da y 1 8 0 [ M 6]). Refer t o Secti o n  7. 3 . 
2.  C hec k c o ntrai n dicati o n s t o trial vacci nati o n (f or Gr o u p 1 o n Da y 1 [ M 0], Da y 9 0 [ M 3] a n d 
Da y 1 8 0 [ M 6], a n d f or Gr o u p 2 o n Da y 1 [ M 0] a n d Da y 1 8 0 [ M 6]). Refer t o Secti o n 7. 5 . 
3.  Vacci n ate t he s u bject. Refer t o Secti o n 8. 1. 3  a n d 8. 2 . 
9. 3. 3  P ost -V acci n ati o n  Pr o ce d ures ( D a y 1 [ M 0], D a y 9 0 [ M 3] a n d D a y 1 8 0 [ M 6])  
P ost -vacci nati o n pr oce d ures will be perf or me d f or all s u bjects ( Gr o u p 1 a n d 2) o n Da y 1 ( M 0), 
u nless ot her wise state d t hese pr oce d ures will be re peate d o n Da y 9 0 ( M 3) f or Gr o u p 1 o nl y, a n d o n 
Da y 1 8 0 ( M 6) f or Gr o u ps 1 a n d 2. 
•  Perf or m p ost -vacci nati o n o bser vati o n (refer t o Secti o n 8. 2. 1 ). 
•  Caref ul trai ni n g of t he s u bject or t he s u bject’s L A R o n h o w t o meas ure s olicite d l ocal 
(i njecti o n site) reacti o ns a n d b o d y te m p erat ur e, h o w t o c o m plete t he diar y car d a n d h o w ofte n 
t o c o m plete t he diar y car d. Trai ni n g s h o ul d be directe d at t he i n di vi d ual(s) w h o will perf or m 
t he meas ure m e nts of s olicite d l ocal (i njecti o n site) reacti o ns a n d t h ose w h o will e nter t he 
i nf or mati o n i nt o t he diar y car d. T his i n di vi d ual ma y or ma y n ot be t he s u bject or t he s u bject’s 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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L A R, b ut if a p ers o n ot her t ha n t he s u bject or t he s u bject’s L A R e nters i nf or mati o n i nt o t he 
diar y car d, t his pers o n’s i de ntit y m ust be d oc u me nte d i n t he s o urce a n d t his pers o n m ust 
recei v e trai ni n g o n t he di ar y car d. Trai ni n g of t h e s u bject or t he s u bject’s L A R o n h o w t o 
meas ure a n i njecti o n site reacti o n a n d h o w t o ta ke t heir te m perat ur e, as w ell as h o w t o rec or d 
t he i nf or mati o n i n t he diar y car d, s h o ul d b e perf or me d w hile t he s u bject is u n der o bser vati o n 
after vacci n ati o n. Trai ni n g of t he s u bj ect or s u bject’s L A R s h o ul d be d o c u me nte d i n t he 
s u bject’s s o urce d oc u me nt. 
Diar y car d i nstr ucti o ns m ust i ncl u de t he f oll o wi n g:  
•  T he i n di vi d ual(s) w h o will e nter t he i nf or mati o n i nt o t he diar y car d m ust u n dersta n d t hat 
ti mel y c o m pleti o n of t he diar y car d o n a dail y basis is a critical c o m p o ne nt of trial 
partici pati o n. T his i n di vi d ual  s h o ul d als o be i nstr ucte d t o write clearl y a n d t o c o m plete t he 
diar y car d i n pe n. A n y c orrecti o ns t o t he diar y car d t hat are perf or m e d b y t he i n di vi d ual(s) 
c o m pleti n g t he diar y car d s h o ul d i ncl u de a si n gle stri ket hr o u g h li ne wit h a brief e x pla nati o n 
f or a n y c h a n ge a n d be i nitiale d a n d date d. 
Pleas e n ote: 
Diar y car ds will be t he o nl y s o urce d oc u me nt all o we d f or re m ote c ollecti o n of s olicite d l ocal 
(i njecti o n site) reacti o ns a n d s olicite d s yste mic A Es (i ncl u di n g b o d y te m p erat ur e meas ure me nts). 
T he f oll o wi n g a d diti o nal r ules a p pl y t o t he d oc u m e ntati o n  of safet y i nf or mati o n c ollecte d b y di ar y 
car d:  
•  T he diar y car d s h o ul d be re vie we d wit h t he s u bject a n d/ or t he s u bject’s L A R.  
•  N o c orrecti o ns or a d diti o ns t o t he diar y car d will be all o we d after it is re vie we d wit h t he 
i n vesti gat or/ desi g nee. 
•  A n y d ata t hat is  i de ntifie d as i m pla usi ble or i nc orrect, a n d c o nfir me d b y t he s u bject a n d/ or t he 
s u bject’s L A R t o be a tr a nscri pti o n err or, s h o ul d b e c orrecte d b y t h e s u bject a n d/ or t he 
s u bject’s L A R o n t he diar y car d (t he c orrecti o n s h o ul d i ncl u de a si n gle stri ket hr o u g h li ne a n d 
s h o ul d be i nitiale d a n d date d b y t he s u bject a n d/ or t he s u bject’s L A R).  
•  A n y bla n k or ille gi ble fiel ds o n t he diar y car d n ot ot her wise c orrecte d as a b o ve will be missi n g 
i n t he e C R F. 
•  T he site m ust e nter all rea da ble e ntri es o n t he diar y car d i nt o t he e C R F.  
•  A n y n e wl y descri be d s olicite d safet y i nf or mati o n s h o ul d be a d de d t o t he diar y car d b y t h e 
s u bject, i nitiale d, a n d date d. A n y ne w u ns olicite d safet y i nf or mati o n w o ul d be rec or de d i n t he 
s u bject s o urce d o c u me nt as a ver ball y re p ort e d e v e nt a n d t heref ore ca pt ur e d as a n A E a n d 
rec or de d i n t he “ A d v erse E ve nt” e C R F. 
•  Starti n g o n t he da y of vacci nati o n, t he s u bject a n d/ or t he s u bject’s L A R will c hec k f or s p ecific 
t y pes of e ve nts at t he i njecti o n site (s olicite d l ocal [i njecti o n site] reacti o ns), a n y s p ecific 
ge n eralize d s y m pt o ms (s olicite d s yste mic A Es), b o d y te m perat ur e (a n y r o ute ma y be use d; t he 
sa me r o ute s h o ul d c o nsiste ntl y be use d f or te m perat ure meas ure me nt), a n y ot her s y m pt o ms or 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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c ha n ge i n t he s u bject’s h ealt h stat us, a n d a n y me dicati o ns ta ke n (e x cl u di n g vita mi ns a n d 
mi nerals). T hese s olicite d A Es (s olicite d l ocal [i njecti o n site] reacti o ns or s olicite d s yste mic 
A Es) a n d b o d y te m perat ure will be rec or de d i n t h e diar y. Assess me nts s h o ul d prefera bl y ta ke 
place i n t he e v e ni n g at da y’s e n d.  
•  B o d y te m perat ure meas ure me nt is t o be perf or me d usi n g t he t her m o meter pr o vi de d b y t h e site. 
If t he s u bject f eels u n us u all y h ot or c ol d d uri n g t h e da y, t he s u bject s h o ul d c hec k t heir 
te m perat ur e. If t he s u bject has fe ver, t he hi g h est b o d y te m perat ure o bs er ve d t hat da y s h o ul d be 
rec or de d i n t he diar y car d. 
•  T he meas ur e me nts of s olicite d l ocal (i njecti o n site) reacti o ns ( pai n, er yt h e ma, a n d s welli n g) 
are t o be p erf or me d usi n g t he r ul er pr o vi de d b y t h e site.  
•  T he diar y car ds will be re vie we d a n d c ollecte d o n Da y 3 0 ( M 1) ( Gr o u ps 1 a n d 2) a n d o n 
Da y  1 2 0 ( M 4) ( Gr o u p 1).  
•  I n t he di ar y car d, t he c ollecti o n of s olicite d l ocal (i njecti o n site) reacti o ns, a n d s olicite d 
s yste mic A Es (i ncl u di n g b o d y te m perat ur e meas ure me nt) a n d u ns olicite d A Es ( n o n -seri o us) 
will c o nti n ue f or a t otal of 7 da ys, 1 4 da ys, a n d 2 8 da ys; res pecti vel y, f oll o wi n g a d mi nistrati o n 
of trial vacci ne d ose (i n cl u di n g t he da y of a d mi nistrati o n) o n Da y 1 ( M 0) i n Gr o u ps 1 a n d 2, 
a n d o n Da y 9 0 ( M 3) i n Gr o u p 1 o nl y. A n y s olicite d l ocal (i njecti o n site) reacti o n or s olicite d 
s yste mic A Es o bs er ve d as c o nti n ui n g o n Da y 8 or Da y 1 5, res p ecti vel y, f oll o wi n g trial 
vacci nati o n o n D a y 1 ( M 0) i n Gr o u ps 1 a n d 2, a n d o n Da y 9 0 ( M 3) i n Gr o u p 1 o nl y will be 
rec or de d as a n A E o n t he “A d vers e E ve nt” e C R F f or f oll o w -u p. A n y s olicite d l ocal (i njecti o n 
site) reacti o n(s) or s yste mic A E t hat res ol ves b ef ore 8 or 1 5 d a ys, res pecti vel y, f oll o wi n g eac h 
trial vacci nati o n, b ut rec urs at a later ti me (i e, if disc o nti n ue d), s h o ul d be rec or de d as a n 
u ns olicite d A E o n t he “ A d verse E ve nt ” e C R F (se e Secti o ns 1 0. 4. 1  a n d 1 0. 4. 2 ). 
•  Pr o vi de g ui da n ce wit h r es pect t o t he a v oi da nce of pre g na nc y f or fe males of c hil d beari n g 
p ote ntial w h o are s e x uall y acti ve wit h me n. Refer t o Secti o n 9. 1. 9 . 
•  C ollect a n d re p ort S A Es. Refer  t o Secti o n 1 0. 4. 4 . 
After eac h trial v acci n ati o n, t he s u bject will be o bser ve d f or at least 3 0 mi n utes i ncl u di n g 
o bser vati o n f or s olicite d l ocal (i njecti o n site) re acti o ns, s olicite d s yst e mic A Es (i ncl u di n g b o d y 
te m perat ur e meas ure m e nt), a n d u ns olicite d A Es. I nf or mati o n s h o ul d be rec or de d i n t he e C R F. T he 
i n vesti gat or or d ele gat e will ta ke t he o p p ort u nit y t o re mi n d t he s u bject a n d/ or t he s u bject’s L A R  
h o w t o meas ure s olicite d l ocal (i njecti o n site) reacti o ns a n d b o d y te m perat ur e as part of t his 
o bser vati o n peri o d. All s afet y data will be c ollect e d i n t he s u bject’s s o urce d oc u me nts.  
T he i n vesti gat or or del e gate s h o ul d sc he d ule t he n e xt site visit or ot her trial acti vit y wit h t he 
s u bject or t he s u bject’s L A R. 
T he s u bject or s u bje ct’s L A R will recei ve a writte n re mi n der of t he ne xt sc he d ule d trial visit.  
T he s u bject or t he s u bject’s L A R will be re mi n de d t o c o m plete t he diar y car d dail y a n d t o c o ntact 
t he site if t here are a n y q uesti o ns a n d t o c o ntact t h e site i m me diatel y ( or as s o o n as t he s u bject is 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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me dicall y sta bl e) if t he s u bject has a me dical c o n diti o n t hat lea ds t o a h os pitalizati o n or a n 
e mer ge n c y r o o m visit. All c o ntact details will be pr o vi de d t o t he s u bject or s u bject’s L A R.  
9. 3. 4  Site Visits after V acci n ati o n ( D a y 3 0 [ M 1], D a y 1 2 0 [ M 4] a n d D a y 2 1 0 [ M 7]) 
Cli nic visits t hat d o n ot i ncl u de a vacci nati o n will be perf or me d o n Da y 3 0 ( M 1), Da y 1 2 0 ( M 4) 
a n d Da y 2 1 0 ( M 7). T hes e visits s h o ul d occ ur at least 2 9 da ys after t he first T D V a n d 9 v H P V 
vacci nati o ns o n Da y 1 ( M 0), t he s ec o n d T D V v acci nati o n ( Gr o u p 1 o nl y) o n Da y 9 0 ( M 3) a n d t he 
sec o n d 9 v H P V vacci nati o n o n Da y 1 8 0 ( M 6)  (see als o Secti o n 9. 3 ). 
1.  I nter vie w t he s u bject or s u bject’s L A R a n d c h ec k t he diar y car d (f or Gr o u p 1: Da y 3 0 [ M 1] a n d 
Da y 1 2 0 [ M 4]; a n d f or Gr o u p 2: Da y 3 0 [ M 1]). Refer t o Secti o n 9. 3. 3 . 
2.  C ollect i nf or mati o n of c o nc o mita nt me dicati o n(s)/ vacci nati o n(s). R efer t o Secti o n 9. 1. 2 . 
3.  Perf or m a tar gete d p h ysi cal e x a mi nati o n. Refer t o Secti o n 9. 1. 4 . 
4.  C hec k vital si g ns. Refer t o Secti o n 9. 1. 5 . 
5.  Pr o vi de g ui da n ce wit h r es pect t o t he a v oi da nce of pre g na nc y f or fe males of c hil d beari n g 
p ote ntial w h o are s e x uall y acti ve wit h me n. Refer t o Secti o n 9. 1. 9 . 
6.  C ollect a n d rec or d persiste nt/ pr ol o n ge d s olicite d l ocal (i njecti o n site) reacti o ns . Refer t o 
Secti o ns 9. 3. 3  a n d 1 0. 4. 2 . 
7.  C ollect a n d rec or d persiste nt/ pr ol o n ge d s olicite d s yste mic A Es.  Refer t o Secti o ns 9. 3. 3  a n d 
1 0. 4. 2 . 
8.  C ollect a n d rec or d S A Es. Refer t o Secti o n 1 0. 4. 4 . 
9.  C ollect a bl o o d sa m ple fr o m t he s u bject ( Da y 1 2 0 [ M 4] i n Gr o u p 1, a n d Da y 2 1 0 [ M 7] i n 
Gr o u ps 1 a n d 2). Refer t o Secti o n 9. 1. 6 .  
Bl o o d s h o ul d be ta ke n fr o m t he s u bject usi n g a n as e ptic ve ni p u nct ure t ec h ni q ue f or ser ol o gi cal 
i m m u n o ge nicit y testi n g.  
T he i n vesti gat or or del e gate s h o ul d sc he d ule t he n e xt site visit or ot her trial acti vit y wit h t he 
s u bject or t he s u bject’s L AR.  
T he s u bject or s u bje ct’s L A R will recei ve a writte n re mi n der of t he ne xt sc he d ule d trial visit, as 
a p plica ble.  
T he s u bject or t he s u bject’s L A R will be re mi n de d t o c o ntact t he site if t here are a n y q u esti o ns a n d 
t o c o ntact t he site i m me diatel y ( or as s oo n as t he s u bject is me dicall y sta bl e) if t he s u bject has a 
me dical c o n diti o n t hat lea ds t o a h os pitalizati o n or a n e mer ge nc y r o o m visit. All c o ntact details 
will be pr o vi de d t o t he s u bject or s u bject’s L A R.  
9. 3. 5  P h o ne C o nt acts - Re mi n der C alls  
N ot a p plica ble.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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9. 3. 6  P h o ne C o nt acts –  S afet y C all  
W he n a site visit ca n n ot be carrie d o ut d ue t o t he C O VI D -1 9 pa n d e mic, alt er nati ve met h o ds of 
c o ntact (e. g tele p h o n e c o ntact) will be ma de f or s u bjects w h o are still u n der m o nit ori n g f or safet y 
re p orti n g. 
9. 3. 7  Fi n al ( E n d of Tri al) Visit ( D a y 3 6 0 [ M 1 2]) 
T he fi nal (e n d of trial) visit will be perf or me d o n Da y 3 6 0 ( M 1 2). If a s u bj ect ter mi nates earlier, 
t he fi nal visit pr oce d ures s h o ul d be perf or m e d at t heir last trial visit, if p ossi ble. F or all s u bjects 
recei vi n g trial va cci ne(s), t he i n vesti gat or m ust c o m plete t he “ E n d of Trial” e C R F pa ge.   
Re vie w of s yste ms ( Da y 3 6 0 [ M 1 2]: re vie w of s yste ms is a str uct ure d i nter vie w t hat q ueries t he 
s u bject or t he s u bject’s L A R as t o a n y c o m plai nts t he s u bject has e x perie nce d acr oss eac h or ga n 
s ystem.  
9. 3. 8  P ost -Tri al C are  
N o p ost -trial care will be pr o vi de d. 
9. 4  
Bi ol o gic al S a m ple Rete nti o n a n d Destr ucti o n  
I n t his trial, s peci me ns f or i m m u ne res p o nse testi n g will be c ollecte d as des cri be d i n Secti o n 9. 1. 6 . 
All bl o o d sa m ples will be pr ocess e d, la bele d a n d st ore d acc or di n g t o t he La b orat or y Ma n ual or 
ot her a p pr o priate g ui deli ne pr o vi de d t o t he site . Sa m ples will be preser ve d a n d retai ne d at a ce ntral 
la b orat or y t h at was c ontr acte d b y t he s p o ns or f or t his p ur p ose f or u p t o b ut n ot l o n ger t ha n 2 0 years 
or as re q uir e d b y a p plica ble la w. T he s p o ns or h as p ut i nt o place a s yste m t o pr otect t he s u bject’s 
pers o nal i nf or mati o n t o e ns ure o pti mal c o nfi de ntialit y a n d defi n e d sta n dar d p r ocesses f or sa m ple 
a n d data c ollecti o n, st ora ge, a nal ysis, a n d destr u cti o n.  
Ser u m sa m ples will be us e d f or t he a n al ys es defi ne d i n t his pr ot oc ol, b ut ca n als o, wit h per missi o n 
fr o m t he s u bject or s u bject’s L A R , be use d t o assess, i m pr o ve or d e vel o p tests relate d t o d e n g ue  or 
t he i n vesti gati o nal vacci ne ( T D V) t hat will all o w m ore relia ble meas ure me nt of t he res p o nse t o t he 
i n vesti gati o nal va cci ne. 
 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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1 0. 0  
A D V E R S E E V E N T S  
1 0. 1  
Defi niti o ns  
1 0. 1. 1  A d verse E ve nts  
A n A E is defi ne d as a n y u nt o war d me dical o cc urre nce i n a cli nical i n vesti gati o n s u bject 
a d mi nistere d a trial va cci ne; it d oes n ot necessaril y ha v e t o ha ve a ca usal r elati o ns hi p wit h trial 
vacci ne a d mi nistrati o n.  
A n A E ca n t heref ore b e a n y u nfa v ora ble a n d u ni nt e n de d si g n (e g, a cli nicall y si g nifica nt a b n or m al 
la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y ass ociat e d wit h t he a d mi nistrati o n of a trial 
vacci ne w het her or n ot it is c o nsi dere d relate d t o t he trial vacci ne.  
A Es will be gra de d b y t h e i n vesti gat or i n t he f oll o wi n g ma n ner:  
Mil d  
Gra d e 1  
•  
A ware ness of s y m pt o ms t hat are easil y t olerate d, ca usi n g mi ni mal disc o mf ort a n d n ot 
i nterferi n g wit h e ver y da y acti vities. Relie ve d wit h or wit h o ut s y m pt o matic treat me nt. 
M o derate  
Gra d e 2  
•  
S ufficie nt disc o mf ort is prese nt t o ca use i nterfere nce wit h n or mal acti vit y. O nl y 
partiall y relie ve d wit h s y m pt o matic treat me nt.  
Se vere  
Gra d e 3  
•  
E xtre me distress, ca usi n g si g nifica nt i m pair me nt of f u ncti o ni n g or i nca pacitati o n. 
Pre ve nts n or mal e ver y da y acti vities. N ot relie ve d wit h s y m pt o matic treat me nt.  
1 0. 1. 2  S olicite d A d verse E ve nts  
T he occ urre n ce  of s elect e d i n dicat ors of safet y will be meas ure d/c ollecte d f or 7 da ys  (s olicite d 
l ocal [i njecti o n site] reacti o ns) a n d 1 4 da ys (s olicite d s yste mic  A Es) f oll o wi n g  a d mi nistrati o n of 
eac h trial v acci n e d ose (i ncl u di n g t he da y of a d mi nistrati o n) a n d will be rec or de d o n t he “ L ocal 
a n d S yste mic Re acti o ns” e C R F pa ge as a p plica ble a n d as liste d i n  Ta ble  1 0 .a. 
A n y s olicite d l ocal (i njecti o n site ) reacti o ns or s oli cite d s yste mic A Es o bser ve d as c o nti n ui n g o n 
Da y  8 or Da y 1 5, res p ecti vel y, f oll o wi n g eac h trial vacci nati o n will be rec or de d as a n A E o n t he 
“ A d vers e E ve nt” e C R F f or f oll o w -u p.  F or t hese p ersiste nt/ pr ol o n ge d s olicite d A Es t he e n d dat e 
will be ca pt ure d o n t he “ A d verse  E v e nt” e C R F t o per mit a se parate a n al ysis fr o m t he u ns olicite d 
A Es (see Secti o ns 1 0. 4. 1  a n d 1 0. 4. 2 ). 
T a ble  1 0 .a  
S olicite d L oc al (I njecti o n Site) Re acti o ns a n d S yste mic A d verse E ve nts  
L ocal (i nj ecti o n site) reacti o ns  
P ai n  
Er yt he ma  
S welli n g  
S yste mic e ve nts (a d ult/a d oles ce nt/c hil d ≥6 years) 
Fe ver (a) 
Hea dac he  
Ast he nia  
Malaise  
M yal gia  
(a) Fe ver is defi ne d as b o d y te m p erat ure greater t ha n or e q ual t o 3 8° C ( 1 0 0. 4° F) re gar dless of met h o d ta ke n [ 2 0 ]. 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 6 4  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
T he se verit y of s olicite d safet y para meters will be assesse d as d escri be d i n Ta ble  1 0 .b . 
T a ble  1 0 .b  
Se verit y Sc ales f or S olicite d P a r a meters  
A d verse E ve nt  
Se verit y Gr a de  
Se verit y  
P ai n at i nj ecti o n site(s)  
0  
N o ne  
1  
Mil d: N o i nterfere nce wit h dail y acti vit y  
2  
M o derate: I nterfere nce wit h dail y acti vit y wit h or wit h o ut treat me nt 
3  
Se vere: Pre ve nts dail y acti vit y wit h or wit h o ut treat me nt  
Er yt he ma at i nj ecti o n  
site(s) (a) 
0  
< 2 5 m m  
1  
Mil d: > 2 5 –  ≤5 0 m m  
2  
M o derate: > 5 0 –  ≤1 0 0 m m  
3  
Se vere: > 1 0 0 m m  
S welli n g at i nj ecti o n 
site(s) (a) 
0  
< 2 5 m m  
1  
Mil d: > 2 5 –  ≤5 0 m m  
2  
M o derate: > 5 0 –  ≤1 0 0 m m  
3  
Se vere: > 1 0 0 m m  
Hea dac he  
0  
N o ne  
1  
Mil d: N o i nterfere nce wit h dail y acti vit y  
2  
M o derate: I nterfere nce wit h dail y acti vit y wit h or wit h o ut treat me nt  
3  
Se vere: Pre ve nts n or mal acti vit y wit h or wit h o ut treat me nt  
Ast he nia  
0  
N o ne  
1  
Mil d: N o i nterfere nce wit h dail y acti vit y  
2  
M o derate: I nterfere nce wit h dail y acti vit y  
3  
Se vere: Pre ve nts dail y acti vit y  
Malaise  
0  
N o ne  
1  
Mil d: N o i nterfere nce wit h dail y acti vit y  
2  
M o derate: I nterfere nce wit h dail y acti vit y  
3  
Se vere: Pre ve nts dail y acti vit y  
M yal gia  
0  
N o ne  
1  
Mil d: N o i nterfere nce wit h dail y acti vit y  
2  
M o derate: I nterfere nce wit h dail y acti vit y  
3  
Se vere: Pre ve nts dail y acti vit y  
Fe ver ( b) 
Rec or d b o d y te m perat ure i n ° C/° F  
(a) S u bj ects or t he s u bj ect’s le gall y a ut h orize d re prese ntati ves are t o rec or d greatest s urface dia meter i n m m o n t he 
diar y car d.  
( b) Fe ver is defi ne d as b o d y te m p erat ure greater t ha n or e q ual t o 3 8° C ( 1 0 0. 4° F) re gar dless of met h o d ta ke n  [2 0 ]. 
1 0. 1. 3  A d verse E ve nts of S peci al I nterest   
N ot a p plica ble.  
1 0. 1. 4  Me dic all y -Atte n de d A d verse E ve nts  
N ot a p plica ble.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 6 5  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
1 0. 1. 5  Seri o us A d verse E ve nts  
A n S A E is defi ne d as a n y u nt o war d me dical o cc urre nce t hat:  
1.  Res ults i n D E A T H.  
2.  Is LI F E T H R E A T E NI N G. 
•  T he ter m “life t hreate ni n g” refers t o a n e ve nt i n w hic h t he s u bject was at ris k of deat h at t he 
ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt t hat h y p ot heticall y mi g ht ha ve ca use d deat h 
if it were m ore s e vere. 
3.  Re q uires i n patie nt H O S PI T A LI Z A TI O N or pr ol o n gati o n of e xisti n g h os pitalizati o n.  
4.  Res ults i n persiste nt or si g nifica nt DI S A BI LI T Y/I N C A P A CI T Y.  
5.  Lea ds t o a C O N G E NI T A L A N O M A L Y/ BI R T H D E F E C T i n t he offs pri n g of a s u bject.  
6.  Is a n I M P O R T A N T M E DI C A L E V E N T t hat s atisfies a n y of t he f oll o wi n g:  
•  Ma y re q uire i nter ve nti o n t o pre ve nt ite ms 1 t hr o u g h 5 a b o v e.  
•  Ma y e x p ose t he s u bject t o da n ger, e v e n t h o u g h t he e ve nt is n ot i m me diatel y life 
t hreate ni n g or fatal or d o es n ot res ult i n h os pitalizati o n. 
1 0. 2  
C a us alit y of A Es  
Relati o ns hi p (ca usalit y) t o t he trial vacci n e(s) will als o be assesse d b y t h e i n vesti gat or. T he 
relati o ns hi p of eac h A E t o t he trial vacci n e(s), i ncl u di n g s olicite d s yst e mic A Es (s olicite d l ocal 
[i njecti o n site] reacti o ns are c o nsi dere d as rel ate d b y defa ult) will be asse sse d usi n g t he f oll o wi n g 
cate g ories:  
Relate d:  
T here is s us pici o n t hat t here is a relati o ns hi p bet wee n t he trial vacci ne a n d t he 
A E ( wit h o ut deter mi ni n g t he e xte nt of pr o ba bilit y); t here is a reas o na ble 
p ossi bilit y t hat t he trial v acci ne c o ntri b ute d t o t he A E.  
N ot Relate d:  
T here is n o s us pici o n t hat t here is a relati o ns hi p bet wee n t he trial vacci ne a n d t he 
A E; t here are ot her m ore li kel y ca uses a n d a d mi nistrati o n of t he trial vacci ne is 
n ot s us pecte d t o ha ve c o ntri b ute d t o t he A E.  
1 0. 2. 1  Rel ati o ns hi p t o Tri al Pr o ce d ures  
 Relati o ns hi p (ca usalit y) t o trial pr oce d ures s h o ul d be deter mi ne d f or all A Es.  
T he relati o ns hi p s h o ul d be assesse d as “ Yes ” if t he i n vesti gat or c o nsi ders t hat t here is a reas o na ble 
p ossi bilit y t hat a n e v e nt is d ue t o a trial pr oce d ure. Ot her wise, t he relati o ns hi p s h o ul d be assesse d 
as “ N o”.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 6 6  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
1 0. 2. 2  O utc o me of A d verse E v e nts  
Res ol ve d:  
T he s u bject has f ull y rec o vere d fr o m t he e ve nt or t he c o n diti o n has 
ret ur ne d t o t he le vel o bser ve d at bas eli ne.  
Res ol vi n g:  
T he e ve nt is i m pr o vi n g b ut t he s u bject is still n ot f ull y rec o vere d.  
N ot res ol ve d:  
T he e v e nt is o n g oi n g at t he ti me of re p orti n g a n d t he s u bject has still n ot 
rec o vere d. 
Res ol ve d wit h 
se q uelae: 
As a res ult of t he A E, t he s u bject s uffere d persiste nt a n d si g nifica nt 
disa bilit y/i nca pacit y (e g, beca me bli n d, deaf or p aral yze d).  
Fatal:  
T he s u bject die d d ue t o t he e ve nt. If t he s u bject di e d d ue t o ot her 
circ u msta nces t ha n t he e ve nt, t he o utc o me of t he e ve nt per s e s h o ul d be 
state d ot her wise (e g, n ot res ol ve d or res ol vi n g). 
U n k n o w n:  
If o utc o me is n ot k n o w n or n ot re p orte d.  
1 0. 3  
A d diti o n al P oi nts t o C o nsi der f or A d verse E ve nts  
A n u nt o war d occ urre nce ge n erall y ma y:  
•  I n dic ate a n e w dia g n osis or u ne x pecte d w orse ni n g of a pre-e xisti n g c o n diti o n. I nter mitte nt 
e ve nts f or pre -e xisti n g c o n diti o ns or u n derl yi n g disease s h o ul d n ot be c o nsi dere d as A Es.  
•  Necessitate t h era p e utic i nter ve nti o n.  
•  Re q uire a n i n vasi ve dia g n ostic pr oce d ure.  
•  Re q uire trial vacci ne disc o nti n uati o n or a c ha n ge i n c o nc o mita nt me dicati o n.  
•  Be c o nsi d ere d u nfa v ora ble b y t he i n v esti gat or f or a n y reas o n.  
Dia g n os es vers us si g ns a n d s y m pt o ms:  
•  Eac h e v e nt s h o ul d be rec or de d t o re prese nt a si n gl e dia g n osis. Acc o m p a n yi n g si g ns (i ncl u di n g 
a b n or mal la b orat or y val u es) or s y m pt o ms s h o ul d N O T be rec or de d as a d diti o nal A Es. If a 
dia g n osis is u n k n o w n, si g ns or s y m pt o ms  s h o ul d be rec or de d a p pr o priat el y as A Es. 
W orse ni n g of A Es:  
•  If t he s u bject e x perie nces a w orse ni n g or c o m plicati o n of a n A E after a d mi nistrati o n of t he trial 
vacci ne, t h e w orse ni n g or c o m plicati o n s h o ul d be rec or de d as a n e w A E. I n vesti gat ors s h o ul d 
e ns ure t hat t he A E ter m rec or de d ca pt ur es t he c ha n ge i n t he c o n diti o n (e g, “ w orse ni n g of …”). 
•  If t he s u bject e x perie n ces a w orse ni n g or c o m plicati o n of a n A E, t he w orse ni n g or 
c o m plicati o n s h o ul d be rec or de d as a n e w A E. I n vesti gat ors s h o ul d e ns ure t hat t he A E te r m 
rec or de d ca pt ures t he c ha n ge i n t he c o n diti o n (e g, “ w orse ni n g of …”). 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 6 7  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
C ha n ges i n s e verit y of A Es:  
•  If t he s u bject e x perie nces c ha n ges i n s e verit y of a n A E, t he e ve nt s h o ul d be ca pt ure d o n ce wit h 
t he ma xi m u m se verit y rec or de d. 
Pre pla n ne d s ur geries or pr oce d ures:  
•  Pre pla n ne d pr oce d ures (s ur geries or t h era pies) t hat were sc h e d ule d pri or t o si g ni n g of 
i nf or me d c o nse nt/ pe diatric asse nt f or m are n ot c o nsi dere d A Es. C o m plicati o ns res ulti n g fr o m 
a n y pl a n ne d s ur ger y s h o ul d be re p orte d as A Es.  
Electi ve s ur geries or p r oce d ures: 
•  Electi ve pr oce d ures p erf or me d w here t here is n o c ha n ge i n t he s u bject’s me dical c o n diti o n 
s h o ul d n ot be rec or de d as A Es, b ut s h o ul d be d oc u me nte d i n t he s u bject’s s o urce d oc u m e nts. 
C o m plicati o ns res ulti n g fr o m a n electi ve s ur ger y s h o ul d be re p or te d as A Es. 
Trial pr oce d ures:  
•  A d verse o cc urre nces rel ate d t o trial pr oce d ures aft er si g ni n g of i nf or me d c o nse nt/ pe diatric 
asse nt f or m are c o nsi dere d as A Es a n d s h o ul d be re p orte d as A Es.  
1 0. 4  
Pr o ce d ures  
1 0. 4. 1  C ollecti o n a n d Re p orti n g of A d verse E ve nts  
All A Es, w het he r c o nsi dere d relate d t o t he use of t he trial vacci n e(s) or n ot, m ust be m o nit ore d 
u ntil s y m pt o ms s u bsi de a n d a n y a b n or mal la b orat or y v al ues ha v e ret ur n e d t o baseli ne, or u ntil 
t here is a satisfact or y e x pla nati o n f or t he c h a n ges o bser ve d, or u ntil deat h, i n w hic h case a f ull 
a ut o ps y re p ort s h o ul d be s u p plie d, if p ossi ble. All fi n di n gs m ust be re p orte d o n a n A E e C R F a n d 
o n t he S A E f or m (a), if necessar y (see Secti o n 1 0. 4. 4 ). All fi n di n gs i n s u bjects e x perie nci n g A Es 
m ust als o be d oc u me nte d i n t he s u bject’s s o urce d o c u me nts. A n y u ns olicite d A Es will be c ollecte d 
f or 2 8 da ys ( da y of v acci nati o n + 2 7 s u bse q ue nt d a ys) f oll o wi n g eac h trial vacci nati o n d uri n g site 
visits via i nte r vie w. A Es lea di n g t o disc o nti n uati o n (fr o m t he trial or fr o m t he vacci nati o n 
re gi me n) are c ollecte d t hr o u g h o ut t he tri al. E ve n if t he s u bject is dee me d i n eli gi ble t o recei ve 
f urt her d oses of trial vacci ne, all eff orts s h o ul d be ma de t o c o nti n ue t he c oll ecti o n of safet y d ata 
acc or di n g t o pr ot o c ol.  
T he f oll o wi n g i nf or mati o n will be d oc u me nte d f or eac h e ve nt:  
•  Re p orte d ter m f or t h e A E.  
•  Start a n d e n d date.  
•  Seri o us ( Y/ N).  
•  Se verit y.  
•  I n v esti gat or’s o pi ni o n of t he ca usalit y (relati o ns hi p) bet wee n t h e e ve nt a n d a d ministrati o n of 
trial vacci ne(s) (“relat e d” or “ n ot relat e d”). 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 6 8  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
•  I n v esti gat or’s o pi ni o n of t he ca usalit y (relati o ns hi p) t o trial pr oce d ure(s), i ncl u di n g t he d etails 
of t he s us pecte d pr oce d ure.  
•  Acti o n ta ke n wit h t he trial vacci ne(s).  
•  O utc o me of e v e nt.  
( a) S A E re p orti n g will be d o ne by e C R F. If t he e C R F syste m is u n av ail a ble, a p a per s p o ns or S A E f or m/ p a per C R F 
s h o ul d be c o m plete d a n d t he eve nt m ust be e ntere d i nt o t he e C R F o nce access is rest ore d.  
1 0. 4. 2  C ollecti o n a n d Re p orti n g of S olicite d A Es  
T he occ urre n ce of s elec t e d i n dicat ors of safet y will be c ollecte d o n diar y car ds b y t he s u bjects or 
s u bjects’ L A R f or 7 da ys (s olicite d l ocal [i njecti o n site] reacti o ns) a n d 1 4 da ys (s olicite d s yste mic 
A Es) f oll o wi n g a d mi nistrati o n of eac h trial vacci ne d ose (i ncl u di n g t he da y o f a d mi nistrati o n) a n d 
will be rec or de d o n t he “ L ocal a n d S yste mic Reacti o ns” e C R F, as a p plica bl e. T hese will be 
s u m marize d i n t he fi nal re p ort u n der t he cate g or y “s olicite d A Es” t o differe ntiate t he m fr o m 
u ns olicite d A Es.  
A n y s olicite d l ocal (i njecti o n si te) reacti o ns or s yste mic A Es o bser ve d as c o nti n ui n g o n Da y 8 or 
Da y 1 5, res p ecti vel y, f oll o wi n g eac h trial v acci n ati o n will be a d diti o nall y rec or de d as a n A E o n 
t he “ A d vers e E ve nt” e C R F f or f oll o w-u p. F or t hese persiste nt/ pr ol o n ge d s olicite d A Es, t he e n d 
date will be ca pt ur e d o n t he “ A d verse E ve nt ” e C R F t o per mit a se p arate a n al ysis fr o m t he 
u ns olicite d A Es.  
A n y s olicite d A E t h at meets a n y of t he f oll o wi n g criteria m ust be e ntere d as a n A E o n t he 
“ A d vers e E ve nt” e C R F p a ge.  
•  S olicite d l ocal (i njecti o n site) reacti o ns or s yste mi c A Es t hat lea d t he s u bject t o wit h dra w fr o m 
t he trial. 
•  S olicite d l ocal (i njecti o n site) reacti o ns or s yste mi c A Es t hat lea d t o t he s u bject bei n g 
wit h dra w n fr o m t he tri al b y t he i n vesti gat or.  
•  S olicite d l ocal (i njecti o n site) reacti o ns o r s yste mi c A Es t hat ot her wise m eet t he defi niti o n of 
a n S A E (see Secti o n 1 0. 1. 2  a n d 1 0. 1. 5 ). 
1 0. 4. 3  C ollecti o n a n d Re p orti n g of A d verse E ve nts of S peci al I nterest / Me dic all y-Atte n de d 
A d verse E ve nts  
A d verse E v e nts of S peci al I nt erest a n d/ or Me dicall y -Atte n de d A d verse E v e nts will n ot be 
c ollecte d. 
1 0. 4. 4  C ollecti o n a n d Re p orti n g of Seri o us A d verse E ve nts  
C ollecti o n of S A Es will c o m me nce fr o m t he ti me t hat t he s u bject is ‘first’ a d mi nistere d t he trial 
vacci ne ( Da y 1 [ M 0]). R o uti ne c ollecti o n of S A Es will c o nti n ue u ntil t he e n d of t he trial ( Da y  3 6 0 
[ M 1 2]). 
S A Es s h o ul d be re p orte d acc or di n g t o  t he f oll o wi n g pr oce d ure: 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 6 9  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
A s p o ns or S A E f or m m ust be c o m plete d (a), i n E n glis h, a n d si g ne d b y t he i n vesti gat or i m me diatel y 
or wit hi n 2 4 h o urs of first o nset or n otificati o n of t he e ve nt. T h e i nf or m ati o n s h o ul d be c o m plete d 
as f ull y as p ossi ble b ut c o ntai n, at a mi ni m u m:  
•  A s h ort descri pti o n of t he e ve nt a n d t he reas o n w h y t he e ve nt is cate g orize d as seri o us.  
•  Ca usalit y assess me nt.  
•  Pr ot oc ol n u m ber.  
•  S u bject i de ntificati o n n u m ber. 
•  I n v esti gat or’s na me. 
•  Na me of trial v acci ne(s).  
T he S A E f or m s h o ul d be tra ns mitte d wit hi n 2 4 h o urs t o f or t he atte nti o n of t he c o ntact(s) i n t h e list 
pr o vi de d t o eac h site.  
( a) S A E re p orti n g will be d o ne by e C R F. If t he e C R F syste m is u n a v ail a ble, a p a per s p o ns or S A E f or m/ p a per C R F 
s h o ul d be c o m plete d a n d t he eve nt m ust be e ntere d i nt o t he e C R F o nce access is rest ore d.  
1 0. 5  
F oll o w -u p Pr oce d ures  
1 0. 5. 1  A d verse E ve nts  
All A Es will be m o nit ore d u ntil res ol uti o n or a sta ble stat us is reac h e d or u ntil a f o r mal dia g n osis 
ca n be ma d e or u ntil t he e n d of t he trial, w hic h e ver occ urs first.  
1 0. 5. 2  Seri o us A d verse E ve nts  
If i nf or mati o n n ot a vaila ble at t he ti me of t he first re p ort bec o mes a vaila bl e later, t he i n vesti gat or 
s h o ul d c o m plete a f oll o w-u p S A E f or m or pr o vi de ot her writte n d oc u me nt ati o n i m me diatel y. 
C o pies of a n y rele v a nt data fr o m t he h os pital n otes (e. g., la b orat or y tests, disc har ge s u m mar y, 
p ost m orte m res ults) s h o ul d be se nt t o t he s p o ns or.  
All S A Es s h o ul d be f oll o we d u p u ntil res ol uti o n, p er ma ne nt o utc o me of t he e ve nt, or is ot her wise 
e x plai ne d. T he ti meli nes a n d pr oce d ure f or f oll o w -u p re p orts are t he s a me as t h ose f or t he i nitial 
re p ort. 
1 0. 5. 3  S afet y Re p orti n g t o I n vesti g at ors, I n vesti g ati o n al Re vie w B o ar ds or I n de pe n de nt 
Et hics C o m mittees, a n d Re g ul at or y A ut h o rities  
T he s p o ns or or d esi g n ee will be res p o nsi ble f or t h e re p orti n g of all S us pect e d U ne x pecte d Seri o us 
A d verse Reacti o ns ( S U S A R) a n d a n y ot her S A Es t o re g ulat or y a ut h orities, i n vesti gat ors  a n d I R Bs 
or I E Cs, as a p plica bl e, i n acc or da nce wit h nati o nal re g ul ati o ns i n t he c o u ntries w here t he trial is 
c o n d ucte d. Relati ve t o t h e first a ware n ess of t he e ve nt b y/ or f urt her pr o visi o n t o t he s p o ns or or 
desi g nee, S U S A Rs will be s u b mitte d wit hi n 7 da ys  f or fatal a n d life-t hr eate ni n g e v e nts a n d 
1 5  da ys f or ot her S U S A Rs, u nless ot her wise re q uire d b y n ati o nal re g ul ati o ns. T he s p o ns or will 
als o pre pare a n e x pe dite d re p ort f or ot h er safet y iss ues w here t hese mi g ht materiall y alter t he 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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c urre nt be n efit -ris k assess me nt of a n i n vesti gati o nal vacci ne or t hat w o ul d be s ufficie nt t o c o nsi der 
c ha n ges i n t he trial vacci ne a d mi nistrati o n or i n t h e o verall c o n d u ct of t h e trial. T he i n vesti gati o nal 
site als o will als o f or war d a c o p y of all e x pe dite d re p orts t o t heir I R B or I E C i n acc or da n ce wit h 
nati o nal re g ulati o ns.  
1 0. 5. 4  P ost -Tri al E ve nts  
A n y S A E t hat o cc urs o utsi de of t he pr ot oc ol -s pecifie d o bser vati o n peri o d or after t h e e n d of t h e 
trial b ut is c o nsi dere d t o be ca use d b y t h e trial vacci ne(s) m ust be re p orte d t o t he s p o ns or.  T hese 
S A Es will be pr ocesse d b y t he s p o ns or’s P har mac o vi gila nce De p art me nt. I nstr ucti o ns f or h o w t o 
s u b mit t hese S A Es will be pr o vi de d i n a ha n d o ut i n t he I n v esti gat or Site Fil e. 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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1 1. 0  
T RI A L -S P E CI FI C R E Q UI R E M E N T( S)  
1 1. 1  
Tri al -S pecific C o m mittees  
1 1. 1. 1  D at a M o nit ori n g C o m m ittee 
A Data M o nit ori n g C o m mittee ( D M C) will ha ve o versi g ht of t his trial. T he D M C f u ncti o ns at a 
pr o gra m le vel a n d f urt her i nf or mati o n is a vaila ble i n t he D M C C harter.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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1 2. 0  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  
T he f ull d etails of pr oce d ures f or d ata h a n dli n g will be d o c u me nte d i n t he Data Ma n a ge me nt Pla n. 
A Es, me dical hist or y, a n d c o nc urre nt me dical c o n diti o ns will be c o de d usi n g t he M e dical 
Dicti o nar y f or Re g ul at or y A cti vities ( Me d D R A) . Dr u gs will be c o de d usi n g t he W H O Dr u g 
Dicti o nar y.  
1 2. 1  
C ase Re p ort F or ms ( El ectr o n ic) 
C o m plete d e C R Fs are re q uire d f or eac h s u bject w h o pr o vi des a si g n e d i nf or me d c o nse nt/ pe di atric 
asse nt f or m.  
T he s p o ns or or desi g nee will s u p pl y i n vesti gati ve sites wit h access t o e C R Fs. T he s p o ns or will 
ma ke arra n ge m e nts t o trai n a p pr o priate site staff  i n t he use of t he e C R F. T hese f or ms are use d t o 
tra ns mit t he i nf or mati o n c ollecte d i n t he perf or ma nce of t his trial t o t he s p o ns or a n d re g ul at or y 
a ut h orities. e C R Fs m ust be c o m plete d i n E n glis h.  
After c o m pleti o n of t he e ntr y pr ocess, c o m p uter l o gic c hec ks  will be r u n t o i de ntif y it e ms, s uc h as 
i nc o nsiste nt dates, missi n g dat a, a n d q uesti o na ble val ues. Q ueri es ma y be iss ue d b y s p o ns or 
pers o n nel ( or d esi g nee[s]) a n d will be a ns w ere d b y t he site.  
C orrecti o ns t o e C R Fs are rec or de d i n a n a u dit trail t hat ca pt ur es t he ol d i nf or mati o n, t he ne w 
i nf or mati o n, i de ntificati o n of t he pers o n ma ki n g t he c orrecti o n, t he date t h e c orrecti o n was ma d e, 
a n d t he reas o n f or c ha n ge.  Reas o ns f or si g nifica nt c orrecti o ns s h o ul d a d diti o nall y be i n cl u de d.  
T he PI m ust re vie w t he e C R Fs f or c o m plete ness a n d acc urac y a n d m ust si g n a n d date t he 
a p pr o priate e C R Fs as i n dicate d. F urt her m ore, t he i n vesti gat or m ust retai n f ull res p o nsi bilit y f or 
t he acc urac y a n d a ut he nti cit y of all data e ntere d o n t he e C R Fs. 
e C R Fs will be re vie we d f or c o m plete n e ss a n d acce pta bilit y at t h e trial site d uri n g peri o dic visits b y 
trial m o nit ors. T he s p o ns or or desi g nee will be per mitte d t o re vie w t he s u bject’s me dical a n d 
h os pital rec or ds perti ne nt t o t he trial t o e ns ure acc urac y of t h e e C R Fs. T he c o m plete d e C R Fs are 
t he s ole pr o pert y of t h e s p o ns or a n d s h o ul d n ot be ma de a vaila ble i n a n y f or m t o t hir d parties, 
e x ce pt f or a ut h orize d re prese ntati ves of a p pr o priat e g o ver n me ntal healt h or re g ulat or y a ut h orities, 
wit h o ut writte n per missi o n of t he s p o ns or.  
W he n a site visit  ca n n ot be carrie d o ut d ue t o t he C O VI D -1 9 pa n d e mic, alt er nati ve met h o ds of 
c o ntact (e. g tele p h o n e c o ntact) will be ma de f or s u bjects w h o are still u n der m o nit ori n g f or safet y 
re p orti n g. Refer als o t o Secti o n 1 4. 1 . 
1 2. 2  
Rec or d R ete nti o n  
T he i n vesti gat or a grees t o kee p t he rec or ds sti p ulate d i n A p pe n di x  A  a n d t h ose d oc u m e nts t hat 
i ncl u de ( b ut are n ot li mite d t o) t he trial-s pecific d oc u me nts, t he i de ntificati o n l o g of all 
partici pati n g s u bj ects, me dical rec or ds. Te m p orar y me dia s u c h as t her m al se nsiti ve pa per s h o ul d 
be c o pie d a n d certifie d, s o urce w or ks heets, all ori gi nal si g ne d a n d d ate d i nf or me d c o nse nt or 
i nf or me d c o nse nt a n d p e diatric asse nt f or ms, s u bj ect a ut h orizati o n f or ms re gar di n g t he use of 
pers o nal he alt h i nf or mati o n (if se parate fr o m t he i nf or me d c o ns e nt or pe diatric asse nt f or ms), 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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electr o nic c o p y of e C R Fs, i ncl u di n g t he a u dit trail, a n d detaile d rec or ds of vacci ne dis p ositi o n t o 
e na ble e v al uati o ns or a u dits fr o m re g ulat or y a ut h orities, t he s p o ns or or desi g nee. F urt her m ore, 
I C H E 6 ( Secti o n 4. 9. 5) re q uires t he i n vesti gat or t o retai n ess e ntial d oc u me nts s pecifie d in I C H  E 6 
( Secti o n 8) u ntil at least 2 years after t he l ast a p pr o val of a mar k eti n g a p plicati o n f or a s p ecifie d 
vacci ne i n dic ati o n bei n g i n vesti gate d or, if a n a p plicati o n is n ot a p pr o ve d, u ntil at least 2  years 
after t he i n v esti gati o n is disc o nti n ue d a n d r e g ulat or y a ut h orities are n otifie d. I n a d diti o n, I C H  E 6 
Secti o n 4. 9. 5 states t hat t he trial rec or ds s h o ul d be retai ne d u ntil a n a m o u nt of ti me s pecifie d b y 
a p plica ble re g ulat or y re q uire me nts or f or a ti me s pecifie d i n t he “ Cli nical St u d y Site A gree me nt ” 
be t wee n t he i n v esti gat or a n d s p o ns or. 
Refer t o t he “ Cli nical St u d y Site A gree me nt” f or t he s p o ns or’s re q uire me nts o n rec or d rete nti o n. 
T he i n vesti gat or s h o ul d c o ntact a n d recei ve writte n a p pr o val fr o m t he s p o ns or bef ore dis p osi n g of 
a n y s u c h d oc u me nts.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
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1 3. 0  
S T A TI S TI C A L M E T H O D S  
1 3. 1  
St atistic al a n d A n al ytic al Pl a ns  
A n S A P will be pre pare d a n d fi nalize d pri or t o dat a base l oc k. T his d oc u m e nt will pr o vi de f urt her 
details re gar di n g t he d efi niti o n of a nal ysis varia bl es a n d a nal ysis met h o d ol o g y t o a d dress all trial 
o bjecti ves . 
A data re vi e w will be c o n d ucte d pri or t o data base l oc k. T his re vie w will assess t he acc urac y a n d 
c o m plete ness of t he tri al data base a n d s u bject e val ua bilit y.  
1 3. 1. 1  A n al ysis Sets  
Safet y s et: t he safet y set will c o nsist of all s u bjects w h o recei ve d at least 1 d o se of T D V or 9 v H P V. 
F ull a nal ysis set ( F A S): t he F A S will i ncl u de all ra n d o mize d s u bjects w h o recei ve d at least 1  d ose 
of trial vacci ne a n d f or w h o m vali d pre -d osi n g ( Da y 0 [ M 0]) a n d at least 1 p ost -d osi n g 
meas ure me nt h a ve bee n recei ve d f or i m m u n o ge nicit y assess me nts.  
Per -pr ot oc ol set ( P P S): t he P P S will e x cl u de all s u bjects ser o p ositi ve f or H P V at Baseli ne a n d will 
i ncl u de all s u bjects i n t he F A S w h o ha ve n o m aj or pr ot oc ol vi olati o ns. T he maj or pr ot oc ol 
vi olati o n criteria will be defi ne d as p art of a d ata re vie w pri or t o t he a nal ysis. T he cate g ories of 
maj or pr ot oc ol vi olati o ns i ncl u de: ( 1) n ot meeti n g selecte d e ntr y criteri a, ( 2) recei vi n g t h e wr o n g 
trial vacci ne, ( 3) recei vi n g pr o hi bite d t hera pies, a n d ( 4) ot her maj or pr ot oc ol vi olati o ns t hat ma y 
be i de nt ifie d d uri n g data re vie ws. 
All s u m maries a n d a nal yses of safet y d ata will be base d o n t he safet y set. T he pri mar y 
i m m u n o ge nicit y a nal yses will be base d o n t he P P S; a d diti o nal i m m u n o ge nicit y a n al ys es ma y be 
pr o vi de d base d o n t he F A S.  
1 3. 1. 2  A n al ysis of De m o gr a p hic s a n d Ot her B aseli ne C h ar acteristics 
A ge, ge n der, race, a n d ot her baseli ne c haracteristics will be s u m marize d descri pti vel y b y trial 
gr o u p f or all ra n d o mize d s u bjects.  
1 3. 1. 3  I m m u n o ge nicit y A n al ysis 
T he pri mar y o bje cti ve, NI of t he i m m u ne res p o nse t o 2 d oses of 9 v H P V vacci ne w he n 
c o nc o mita ntl y a d mi nistere d wit h T D V c o m pare d t o a d mi nistrati o n of 9 v H P V vacci n e al o ne, will 
be assesse d i n ter ms of G M Ts o n Da y 2 1 0 ( M 7). NI f or eac h H P V t y p e will be c o ncl u de d if t he 
u p per b o u n d of t he 9 5 % c o nfi de nce i nter val ( CI) f or t h e G M T rati o ( Gr o u p 2/ Gr o u p 1) is less t ha n 
t he NI mar gi n of 1. 5. O v erall NI will be c o ncl u de d if NI re q uir e me nt is met f or all 9 H P V t y p es, 
t heref ore n o m ulti plicit y a dj ust me nt of first t y pe err or is nee d e d a n d 9 5 % CI will be use d i n eac h 
c o m paris o n.  
Desc ri pti ve statistics i ncl u di n g 9 5 % CI f or t he pri mar y a n d sec o n dar y e n d p oi nts, i ncl u di n g 
ser o p ositi vit y rates a n d G M Ts, will be c o m p ute d b y trial gr o u p f or all a v aila ble assa ys at all 
rele va nt ti me p oi nts. 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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A n a nal ysis of (c o) vari a n ce ( A N[ C O] V A) m o del o n t he nat ural l o garit h ms of titer val ues will be 
use d t o c o m p ute t he 9 5 % CI of t he G M T rati os, wit h trial gr o u p as a fact or base d o n t he P P S. A 
si milar, s u p p orti ve A N C O V A, wit h trial gr o u p as a fact or a n d t he nat ural l o garit h ms of 
pre -vacci nati o n titers as a c o v ari ate ma y be pr o vi de d base d o n t he F A S.  
Ha n dli n g of missi n g data will be descri be d i n t he S A P.  
P ote ntial a nal yses a n d/ or ta ble s u m maries ma y be perf or me d t o assess t he i m pact of t he 
C O VI D -1 9 pa n d e mic. T hese ma y i ncl u de s e nsiti vit y a nal yses i g n ori n g t h e pr ot oc ol -defi ne d visit 
wi n d o ws f or t he P P S s u bjects i m pacte d b y C O VI D -1 9.  
1 3. 1. 4  S afet y A n al ysis  
S olicite d A Es  
Prese nce a n d se verit y ( Gra de) of s olicite d l ocal (i njecti o n site reacti o ns pai n, i njecti o n site 
er yt h e ma a n d i njecti o n site s welli n g) will be c ollecte d usi n g diar y car ds o n Da y 1 ( M 0) a n d 
Da y  9 0 ( M 3) f or 7 da ys f oll o wi n g eac h vacci nati o n. I n Gr o u p 1, reacti o ns o n b ot h i njecti o n sites 
( T D V a n d 9 v H P V vacci n e) will be c ollecte d o n Da y 1 ( M 0) a n d at t he T D V i njecti o n site o n Da y 
9 0 ( M 3). I n Gr o u p 2, reacti o ns  at t he 9 v H P V vacci ne i njecti o n site will be c ollecte d o n Da y 1 
( M 0). 
Prese nce a n d se verit y ( Gra de) of s olicite d s yst e mic A Es (fe ver, ast he nia, m alaise, hea d ac h e a n d 
m yal gia) will be c ollecte d usi n g diar y car ds f or 1 4 da ys f oll o wi n g eac h v acci nati o n. C olle cti o n 
starti n g o n D a y 1 ( M 0) will be f or b ot h i njecti o n sites a n d f or s u bjects i n Gr o u ps 1 a n d 2, a n d 
c ollecti o n starti n g o n Da y 9 0 ( M 3) will o nl y be f or s u bjects i n Gr o u p 1 after t he sec o n d T D V d ose.  
F or eac h s olicite d A E, t h e n u m ber a n d p erce nta ge of s u b jects wit h l ocal (i njecti o n site) reacti o ns 
a n d s yste mic A Es will be s u m mariz e d b y trial gr o u p a n d e ve nt se v erit y f or eac h d a y after trial 
vacci nati o n (ie, D a y 1 t hr o u g h Da y 7 f or l ocal [i njecti o n site] reacti o ns a n d Da y 1 t hr o u g h Da y  1 4 
f or s yst e mic A Es), a n d o verall. S u m maries of first o nset of eac h e ve nt a n d t he n u m ber of d a ys 
s u bjects re p orte d e x perie nci n g eac h e ve nt will als o be rec or de d. F or s u bjects wit h m ore t ha n 
1  e pis o de of t he sa me e v e nt, t he ma xi m u m se verit y will be use d f or ta b ulati o ns.  
Persist e nt/ pr ol o n ge d s oli cite d l ocal reacti o ns or s yste mic A Es c o nti n ui n g o n Da y 8 or Da y 1 5, 
res pecti vel y, f oll o wi n g trial vacci nati o n will be assesse d se paratel y. U nless ot her wise s pecifie d 
t hese reacti o ns or A Es will n ot be i ncl u de d i n t he a nal yses/ta b ul ati o ns of u ns olicite d A Es a n d will 
ha ve se parate listi n gs.  
U ns olicite d A Es  
U ns olicite d A Es will be assesse d f or 2 8 d a ys f oll o wi n g trial vacci nati o n ( da y of vacci nati o n + 
2 7  da ys).  
U ns olicite d A Es will be c o de d usi n g Me d D R A, a n d s u m marize d b y Preferre d Ter m ( P T)  a n d 
S yste m Or ga n Class ( S O C) f or eac h trial gr o u p.  
U ns olicite d A Es will be s u m mariz e d as f oll o ws: b y P T i ncl u di n g e ve nts wit h fre q ue n c y greater 
t ha n a pre-defi ne d fre q u e nc y (t he perce nt a ge will be s pecifie d i n t he S A P); b y S O C a n d P T; b y 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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Tri al N o. D E N -3 0 8  
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S O C, P T, a n d se v erit y; a n d b y S O C, P T, a n d relati o ns hi p t o t he trial vacci ne(s). S u bjects re p orti n g 
m ore t ha n 1 occ urre n ce f or t he ter m (le v el) bei n g s u m marize d will be c o u nte d o nl y o nce.  
A Es lea di n g t o trial or vacci ne wit h dra wal or trial disc o nti n uati o n will be c ollect e d a n d 
s u m marize d f or t he e ntire trial.  
S A Es  
S A Es will be c ollecte d t hr o u g h o ut t he trial. S A Es will be c o d e d usi n g M e d D R A, a n d s u m marize d 
b y P T a n d S O C f or eac h trial gr o u p.  
1 3. 2  
I nteri m A n al ysis a n d Criteri a f or E arl y Ter mi n ati o n 
A n i nteri m a nal ysis of i m m u n o ge nicit y a n d s afet y data is pla n ne d w he n all s u bjects ha ve 
c o m plete d t he Da y 2 1 0 ( M 7) visit. T his will be re p orte d i n a n i nteri m C S R. A fi nal C S R will be 
pre pare d u p o n trial c o m pleti o n t o i ncl u de safet y dat a c ollecte d u p t o t he e n d of t he trial o n Da y 3 6 0 
( M 1 2) a n d will als o i ncl u de res ults f or t he w h ole trial d urati o n. 
Please see Secti o n 7. 4  f or criteria f or earl y ter mi n ati o n. 
1 3. 3  
Deter mi n ati o n of S a m ple Size  
T he sa m ple siz e calc ulati o n ass u mes a si g nifica nce le vel of 0. 0 2 5 ( o n e-si de d). 
F or t he pri mar y o bje cti ve of s h o wi n g NI of 9 v H P V G M Ts, t he calc ulati o n ass u mes a NI mar gi n of 
1. 5, a tr ue G M T rati o of 1 bet wee n trial gr o u ps at Da y 2 1 0 ( M 7), a n d t hat t he nat ural l o garit h ms of 
t he a nti b o d y titers a gai nst 9 H P V t y pes are i n de pe n de nt n or mall y distri b ute d wit h sta n dar d 
de viati o ns of 0. 9 5, 0. 8 6, 0. 9 8, 0. 9 1, 0. 9 8, 0. 9 4, 1. 0 9, 1. 0 3, a n d 0. 9 4. T he lar gest varia bilit y 1. 0 9 
was ass u me d a n d us e d f or sa m ple siz e calc ulati o ns f or all 9 strai ns.  
A sa m ple siz e of 3 0 7 s u bjects per gr o u p, wit h a p pr o xi matel y 2 6 1 e v al ua ble s u bjects per trial gr o u p 
(a dj uste d f or a p pr o xi matel y 1 5 % s u bj ects n ot e val ua ble f or t he i m m u n o ge nicit y assess me nts), is 
s ufficie nt t o ac hie v e a p pr o xi matel y 9 0 % p o wer f or sh o wi n g NI f or t h e pri mar y o bj ecti ve.  
Sa m ple siz e calc ulati o ns were p erf or me d usi n g n Q uer y A d vis or ®  versi o n 8.  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 7 7  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
1 4. 0  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
1 4. 1  
Tri al -Site M o nit ori n g Visits  
M o nit ori n g visits t o t he trial site will be ma de peri o dicall y d uri n g t he trial  t o e ns ure t hat all as pects 
of t he pr ot oc ol are f oll o w e d. S o urce d o c u me nts will be re vie we d f or verificati o n of data rec or de d 
o n t he e C R Fs. S o urce d o c u me nts are d efi ne d as ori gi nal d oc u me nts, dat a, a n d rec or ds. T h e 
i n vesti gat or a n d i nstit uti o n g uara nte e access t o s o urce d oc u m e nts b y t h e s p o ns or or desi g nee 
(cli nical res earc h or ga niz ati o n ) a n d b y t he I R B or I E C. 
All as pects of t he tri al a n d its d oc u me ntati o n will be s u bject t o re vi e w b y t he s p o ns or or desi g n ee, 
i ncl u di n g b ut n ot li mite d t o t he I n v esti gat or Site File, trial vacci n e(s) rec or ds, s u bject me dical 
rec or ds, i nf or me d c o ns e nt/ pe diatric asse nt f or m d o c u me ntati o n, d oc u me ntati o n of s u bject 
a ut h orizati o n t o use pers o nal healt h i nf or mati o n (if se parat e fr o m t he i nf or me d c o nse nt/ pe diatric 
asse nt f or ms), a n d  re vie w of e C R Fs a n d ass ociat e d s o urce d o c u me nts. It is i m p orta nt t hat t he 
i n vesti gat or a n d ot her tri al pers o n nel are a v aila ble d uri n g t he m o nit ori n g visits a n d t hat s ufficie nt 
ti me is de v ote d t o t he pr ocess. 
I n t he e ve nt a m o nit or ca n n ot visit t he site i n a ti mel y ma n ner d ue t o t he C O VI D -1 9 p a n de mic, 
alter nati ve m o nit ori n g a p pr oac hes s u c h as re m ote s o urce dat a verifi cati o n or tele p h o ne c o nt act 
ma y b e use d t o e ns ure data q ualit y a n d i nte grit y a n d mai ntai n s u bject safet y. Alter n ati ve 
m o nit ori n g a p pr oac hes s h o ul d be use d o nl y w here all o we d b y t he l ocal Healt h A ut h orit y a n d w he n 
a p pr o ve d b y t he I R B/I E C. D uri n g re m ote m o nit ori n g, t he m o nit or s h o ul d f oc us o n trial acti vities 
t hat are ess e ntial t o t he safet y of trial s u bjects a n d/ or data relia bilit y. 
1 4. 2  
Pr ot oc ol D e vi ati o ns  
T he i n vesti gat or s h o ul d n ot de viate fr o m t he pr ot o c ol, e xce pt w here n ecessar y t o eli mi nate a n 
i m me diate hazar d t o trial s u bjects. S h o ul d ot her u ne x pecte d circ u msta nces arise t hat will re q uir e 
de viati o n fr o m pr ot oc ol -s pecifie d pr oce d ures, t he i n vestigat or s h o ul d c o ns ult wit h t he me dical 
m o nit or (a n d I R B or I E C, as re q uire d) t o deter mi ne t he a p pr o priat e c o urse of acti o n. T here will be 
n o e x e m pti o ns (a pr os pecti ve a p pr o ve d d e viati o n) fr o m t he i ncl usi o n or e x cl usi o n criteria.  
1 4. 3  
Q u alit y Ass ur a nce A u dits a n d  Re g ul at or y A ge nc y I ns pecti o ns  
T he trial site als o ma y be s u bject t o q ualit y ass ur a nce a u dits b y t he s p o ns or or desi g n ee. I n t his 
circ u msta nce, t he s p o ns or -desi g nate d a u dit or will c o ntact t he site i n a d va n ce t o arra n ge a n 
a u diti n g visit. T he a u dit or ma y as k t o visit t he facilities w here la b orat or y sa m ples are c ollecte d, 
w here t he v acci ne is st ore d a n d pre p are d, a n d a n y ot her facilit y use d d uri n g t he trial. I n a d diti o n, 
t here is t he p ossi bilit y t hat t his trial ma y be i ns pe cte d b y re g ulat or y a ge n ci es, i ncl u din g t h ose of 
f orei g n g o ver n me nts (e. g., t he F o o d a n d Dr u g A d mi nistrati o n [ F D A], t he Me dici nes a n d 
Healt hcare Pr o d ucts Re g ulat or y A ge nc y of t he U nite d Ki n g d o m [ M H R A], t he P har mace uticals 
a n d Me dic al D e vices A ge nc y of J a pa n [ P M D A]). If t he trial site is c o nta cte d f or a n i ns p ecti o n b y a 
re g ulat or y b o d y, t he s p o ns or s h o ul d be n otifie d i m me diatel y. T h e i n vesti gat or a n d i nstit uti o n 
g uara nte e access f or q u alit y ass ura n ce a u dit ors t o all trial d oc u me nts as descri be d i n Secti o n  1 4. 1 . 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 7 8  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
1 4. 4  
Tri al Ris k M a n a ge me nt  
T he I C H E 6 a d d e n d u m ( R 2) g ui da n ce e n c o ura ges a ris k -base d a p pr oac h t o t he ma na ge me nt of 
cli nical trials a n d i ncl u des re q uire me nts f or ris k c o ntr ol a n d ris k re p orti n g. Ta ke da or desi g nee 
( C R O) has esta blis he d q ualit y t olera n ce li mits ( Q T L), t a ki n g i nt o c o nsi d erati o n t he me dical a n d 
statistical c haracteristics of t he varia bl es a n d t he statistical desi g n of t his tri al. T his pr ocess w as 
perf or me d acc or di n g t o Ta ke d a i nter nal pr oce d ures.  
At t he e n d of t he trial, t h e q ualit y ma n a ge me nt a p pr oac h i m ple me nte d will be descri b e d i n t he 
C S R. If a p plica bl e, t he C S R will s u m marize i m p orta nt de viati o ns fr o m t he pre defi n e d Q T L a n d 
t he re me dial a cti o ns ta ke n. 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 7 9  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
1 5. 0  
E T HI C A L A S P E C T S O F T H E T RI A L  
T his trial will be c o n d uct e d wit h t he hi g hest res p ect f or t he tri al s u bjects acc or di n g t o t he pr ot oc ol, 
t he et hical pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki, a n d t he I C H Har m o nise d 
Tri partite G ui deli ne f or G C P [ 2 ]. Eac h i n vesti gat or will c o n d uct t he trial acc or di n g t o a p plica bl e 
l ocal or re gi o n al re g ulat or y re q uire m e nts a n d ali g n his or her c o n d u ct i n acc or da nce wit h t he 
“ Res p o nsi bil ities of t he I n vesti gat or ” t hat are liste d i n A p pe n di x  A . T he pri nci ples of Helsi n ki are 
a d dresse d t hr o u g h t h e pr ot oc ol a n d t hr o u g h a p pe n dices c o ntai n i n g re q uir e me nts f or i nf or me d 
c o nse nt a n d i n vesti gat or res p o nsi bilities.  
1 5. 1  
I nstit uti o n al Re vie w B o ar d a n d/ or I n de pe n de nt Et hics C o m mittee A p pr o v al  
I R Bs a n d I E Cs m ust be c o nstit ute d acc or di n g t o t he a p plica ble l ocal re q uir e me nts of eac h 
partici pati n g re gi o n. T he s p o ns or or desi g nee will re q uire d o c u me ntati o n n oti n g all na mes a n d 
titles of me m bers w h o ma ke u p t he res pecti ve I R B or I E C. If a n y me m ber of t he I R B or I E C has 
direct partici pati o n i n t his trial, writte n n otificati o n re gar di n g his or her a bsti ne nce fr o m v oti n g 
m ust als o be o btai ne d.  
T he s p o ns or or desi g nee will s u p pl y rele va nt d oc u me nts f or s u b missi o n t o t he res pecti ve I R B or 
I E C f or t he pr ot oc ol’s re vie w a n d a p pr o val. T his pr ot oc ol, t he I B, a c o p y of t he i nf or me d c o ns e nt 
a n d pe diatric asse nt f or m, a n d, if a p plica ble, s u bj ect recr uit me nt materials a n d/ or a d vertise me nts 
a n d ot her d oc u me nts r e q uire d b y all a p plica ble l a ws a n d re g ulati o ns, m ust be s u b mitte d t o a 
ce ntral or l ocal I R B or I E C f or a p pr o val. T he I R B’s or I E C’s writte n a p pr o v al of t he pr ot oc o l a n d 
s u bject i nf or me d c o ns e nt a n d/ or pe diatric asse nt f or m m ust be o btai ne d a n d s u b mitte d t o t he 
s p o ns or or desi g n ee b ef ore c o m me nce me nt of t he trial (i.e., bef ore s hi p me nt of t he trial vacci ne(s) 
or trial s pecific s cree ni n g acti vit y). T h e I R B or I E C a p pr o val m ust refer t o t he trial b y e x act 
pr ot oc ol title, n u m ber, a n d versi o n date; i de ntif y v ersi o ns of ot her d oc u me nts (e. g.,  i nf or me d 
c o nse nt a n d/ or pe di atric asse nt f or m) re vie we d; a n d state t he a p pr o val date. T he s p o ns or will 
n otif y t he site o n ce t he s p o n s or has c o nfir me d t he a de q uac y of site re g ulat or y d o c u me ntati o n a n d, 
w he n a p plica bl e, t he s p o ns or has recei ve d per missi o n fr o m t he c o m pete nt a ut h orit y t o be gi n t he 
trial. U ntil t he site recei v es n otificati o n n o pr ot oc ol acti vities, i ncl u di n g scree ni n g ma y occ ur.  
Sites m ust a d here t o all r e q uire me nts sti p ulate d b y t heir res pecti ve I R B or I E C. T his ma y i ncl u de 
n otificati o n t o t he I R B or I E C r e gar di n g pr ot oc ol a me n d me nts, u p dates t o t he i nf or me d c o ns e nt 
a n d/ or pe diatric asse nt f or m, recr uit me nt materials i nte n de d f or vie wi n g b y s u bjects, l ocal safet y 
re p orti n g re q uir e me nts, r e p orts a n d u p dates re gar di n g t he o n g oi n g re vi e w of t he trial at i nter vals 
s pecifie d b y t he res pecti ve I R B or I E C, a n d s u b missi o n of t he i n vesti gat or’s fi nal stat us re p ort t o 
I R B or I E C. All I R B a n d I E C a p pr o vals a n d rele va nt d oc u me ntati o n f or t h ese ite ms m ust be 
pr o vi de d t o t he s p o ns or or desi g n ee.  
I n ce nti ves s h o ul d n ot be use d t o e x ert u n d ue i nfl ue nce o n s u bjects f or partici pati o n. Pa y me nts t o 
s u bjects m ust be a p pr o ve d b y t he I R B or I E C a n d s p o ns or. 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 8 0  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
1 5. 2  
S u bject I nf or m ati o n, I nf or me d C o nse nt/ Pe di at ric Asse nt, a n d S u bject A ut h oriz ati o n  
Writte n c o nse nt d oc u me nts will e m b o d y t h e ele m e nts of i nf or me d c o ns e nt/ pe diatric asse nt as 
descri be d i n t he Declarati o n of Helsi n ki [ 1 ] a n d t he I C H Tri p artite G ui deli nes f or G C P [2 ] a n d will 
be i n acc or da nce wit h all a p plica ble la ws a n d  re g ulati o ns. T he i nf or me d c o nse nt/ pe diatric asse nt 
f or m, a n d s u bject i nf or m ati o n s heet descri b e t he pla n ne d a n d per mitte d uses, tra nsfers, a n d 
discl os ures of t he s u bject’s pers o nal healt h i nf or mati o n f or t he p ur p ose of c o n d ucti n g t he trial. T he 
i nf or me d co ns e nt/ pe diatric asse nt f or m a n d t he s u bject i nf or mati o n s h eet f urt her e x plai n t he n at ure 
of t he trial, its o bjecti ves, a n d p ote ntial ris ks a n d b e nefits, as well as t h e dat e i nf or me d 
c o nse nt/ pe diatric asse nt is gi ve n. T h e i nf or me d c o nse nt/ pe diatric asse nt f or m will detail t he 
re q uire me nts of t h e s u bject a n d t he fact t hat t he s u bject/s u bject’s L A R is free t o wit h dra w t heir 
c hil d at a n y ti me wit h o ut gi vi n g a reas o n a n d wit h o ut prej u dice t o t he s u bject’s f urt her m e dical 
care.  
T he i n vesti gat or s h o ul d assess t he  nee d f or re -c o ns e nt/re-affir mati o n of c o nse nt i n sit uati o ns 
w herei n t here has b ee n s u bsta ntial c ha n ges t o t he s u bject’s stat us of c o n diti o n si nce t he ori gi nal 
c o nse nt. T he pr ocess s h o ul d c o m pl y wit h rele va nt l ocal re g ulati o ns.  
T he i n vesti gat or is res p o nsi ble f or t he pre p arati o n, c o nte nt, a n d I R B or I E C a p pr o val of t he 
i nf or me d c o nse nt/ pe diatric asse nt f or m. T he i nf or me d c o nse nt/ pe diatric asse nt f or m, a n d s u bject 
i nf or mati o n s heet m ust be a p pr o ve d b y b ot h t he I R B or I E C a n d t he s p o ns or pri or t o use. 
T he i nf or me d c o ns e nt/ pe diatric asse nt f or m, a n d s u bject i nf or mati o n s heet m ust be writte n i n a 
la n g u a ge f ull y c o m pr e he nsi ble t o t he pr os pecti ve s u bject/s u bject’s L A R. It is t he res p o nsi bilit y of 
t he i n vesti gat or t o e x plai n t he detaile d ele me nts of t he i nf or me d c ons e nt/ pe diatric asse nt f or m, 
s u bject a ut h oriz ati o n f or m (if a p plica ble), a n d s u bject i nf or mati o n s heet (if a p plica ble) t o t he 
s u bject/s u bject’s L A R. I nf or mati o n s h o ul d be gi v e n i n b ot h oral a n d writte n f or m w he ne v er 
p ossi ble a n d i n t he ma n ner dee m e d a p pr o p riate b y t he I R B or I E C. I n t he e ve nt t he s u bject is n ot 
ca pa ble of re n deri n g a d e q uate writte n i nf or me d c o nse nt, t he n t he s u bject’s L A R ma y pr o vi de s uc h 
c o nse nt f or t he s u bject i n acc or da nce wit h a p plica ble la ws a n d re g ulati o ns (e. g., pe diatri c asse nt 
f or m). 
T he s u bject/s u bject’s L A R m ust be gi ve n a m ple o p p ort u nit y t o: ( 1) i n q uire a b o ut details of t he trial 
a n d ( 2) deci de w h et her or n ot t o (all o w t he c hil d t o) partici pate i n t he tri al. If t he s u bject, or 
s u bject’s L A R, deter mi n es he, s he or t h eir c hil d will partici pate i n t he trial, t he n t he i nf or me d 
c o nse nt/ pe diatric asse nt f or m m ust be si g ne d a n d date d b y t he s u bject/t he s u bject’s L A R, at t he 
ti me of c o nse nt a n d pri or t o t he s u bject e nteri n g i nt o t he trial. T he s u bject or t he s u bject’s L A R 
s h o ul d be i nstr ucte d t o si g n usi n g t heir le gal na mes, n ot nic k na mes, usi n g bl ue or blac k ball p oi nt 
i n k. T he i n vesti gat or m ust als o si g n a n d dat e t he i nf or me d c o nse nt/ pe diatric asse nt at t he ti me of 
c o nse nt a n d pri or t o t he s u bject e nteri n g i nt o t he trial; h o we ver, t h e s p o ns or ma y all o w a desi g nee 
of t he i n vesti gat or t o si g n t o t he e xte nt per mitte d b y a p plica ble la w.  
O nce si g ne d, t he ori gi n al i nf or me d c o nse nt/ pe diatric asse nt f or m, a n d s u bject i nf or mati o n s heet 
will be st ore d i n t he i n vesti gat or’s site file. T h e i n vesti gat or m ust d oc u me nt t he date t he 
s u bject/s u bject’s L A R si g ns t he i nf or me d c o nse nt/ pe diatric asse nt f or m i n t he s u bject’s me dical 
rec or d a n d e C R F. C o pies of t he si g n e d i nf or me d c o nse nt/ pe diatric asse nt f or m, t he si g ne d s u bject 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

De n g ue Tetr a v ale nt V acci ne ( Li ve, Atte n u ate d)  
 
Tri al N o. D E N -3 0 8  
P a ge 8 1  of 8 7  
Pr ot oc ol Versi o n 5 . 0 
0 3  M arc h 2 0 2 1  
 
C O N FI D E N TI A L  
 
a ut h orizati o n f or m (if a p plica ble), a n d s u bject i nf or mati o n s heet (if a p plica ble) s hall be gi ve n t o 
t he s u bject. 
All re vise d i nf or me d c o nse nt/ pe diatric asse nt f or ms m ust be re vie we d a n d si g ne d b y t he s u bject/ 
s u bject’s L A R i n t he sa me ma n ner as t he ori gi nal i nf or me d c o nse nt/ pe diatri c asse nt f or m. T he date 
t he re vise d c o ns e nt was o btai ne d s h o ul d be rec or de d i n t he s u bject’s me dical rec or d a n d e C R F, 
a n d t he s u bject s h o ul d recei ve a c o p y of t he re vise d i nf or me d c o nse nt/ pe diatric asse nt f or m.  
1 5. 3  
S u bject C o nfi de nti alit y  
T he s p o ns or a n d d esi g n ee affir m a n d u p h ol d t he pri nci ple of t he s u bject’s ri g ht t o pr otecti o n 
a gai nst i n vasi o n of pri vac y. T hr o u g h o ut t his trial, a s u bject’s s o urce data will o nl y be li n ke d t o t he 
s p o ns or’s cli nical trial d at a base or d oc u me nt ati o n via a u ni q ue i d e ntificati o n n u m ber. As p er mitte d 
b y all a p plica ble la ws a n d re g ulati o ns, li mite d s u bject attri b utes, s uc h as se x, a ge, or date of birt h, 
a n d s u bject i nitials ma y b e use d t o verif y t he s u bj ect a n d acc urac y of t he s u bject’s u ni q ue 
i de ntificati o n n u m ber. 
T o c o m pl y wit h I C H G ui deli nes f or G C P a n d t o verif y c o m plia nce wit h t his pr ot oc ol, t he s p o ns or 
re q uires t he i n vesti gat or t o per mit its m o nit or or desi g nee, re pres e ntati ves fr o m a n y re g ulat or y 
a ut h orit y (e. g., F D A, M H R A, P M D A), t he s p o ns or’s desi g nate d a u dit ors, a n d t he  a p pr o priate 
I R Bs a n d I E Cs t o re vie w t he s u bject’s ori gi nal me dical rec or ds (s o urce dat a or d oc u me nts), 
i ncl u di n g, b ut n ot li mite d t o, la b orat or y test res ult re p orts, electr ocar di o gra m ( E C G) re p orts, 
a d missi o n a n d disc har ge s u m maries f or h os pital a d missi o n s occ urri n g d uri n g a s u bj ect’s trial 
partici pati o n, a n d a ut o ps y re p orts. Access t o a s u bject’s ori gi nal me dical r ec or ds re q uir es t he 
s pecific a ut h orizati o n of t he s u bject/s u bject’s L A R as part of t he i nf or m e d c o nse nt/ pe diatric asse nt 
f or m pr ocess (see Secti o n 1 5. 2 ). 
C o pies of a n y s u bject s o urce d oc u m e nts t hat are pr o vi de d t o t he s p o ns or m ust ha ve cert ai n 
pers o nall y i de ntifia bl e i nf or mati o n re m o ve d (i.e ., s u bject na me, a d dress, a n d ot her i de ntifier fiel ds 
n ot c ollecte d o n t he s u bject’s e C R F).  
1 5. 4  
Cli nic al Tri al Re gistr ati o n, P u blic ati o n a n d Discl os ure P olic y  
1 5. 4. 1  Cli nic al Tri al Re gistr ati o n  
I n or der t o e ns ure t hat i nf or mati o n o n cli nical trials reac h es t he p u blic i n a ti mel y ma n ner a n d t o 
c o m pl y wit h a p plic a ble la w, re g ulati o n a n d g ui d a nce, t he s p o ns or will, as a mi ni m u m re gister all 
cli nical trials c o n d ucte d i n s u bjects t hat it s p o ns ors a n y w here i n t he w orl d, o n p u blicl y accessi ble 
we bsites s uc h as Cli nical Trials . g o v a n d E u dra C T, acc or di n g t o l ocal re q uir e me nts, bef ore trial 
i nitiati o n. T he s p o ns or c o ntact i nf or mati o n, al o n g wit h t he i n vesti gat or’s cit y, c o u ntr y, a n d 
recr uiti n g stat us will be re gistere d a n d a vaila ble f or p u blic vie wi n g. 
1 5. 4. 2  Cli nic al Tri al Res ults Disc l os ure 
Ta ke da discl os ur e p olic y ai ms t o c o m pl y wit h t he cli nical trial data discl os ure re q uir e me nts of all 
rele va nt r e gi o ns. T he s p o ns or will p ost t he res ults of t his cli nical trial re gar dless of o utc o me, o n 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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p u blicl y accessi ble we bsites s uc h as Cli nical Tri als. g o v a n d/ or E u dra C T, as re q uire d b y a p plica ble 
la ws a n d/ or re g ulati o ns. 
C o m pleti o n of trial c orres p o n ds t o t he date o n w hi c h t he fi n al s u bject was e x a mi ne d or recei ve d a n 
i nter ve nti o n f or t he p ur p ose of fi nal c ollecti o n of data ( us uall y c orres p o n d t o Last S u bject Last 
Visit).  
I n case t h e dea dli ne f or res ults discl os ure ca n n ot be met, a n a p plicati o n f or e xte nsi o n wit h 
scie ntific j ustificati o n will be i nitiate d. 
1 5. 4. 3  P u blic ati o n of Tri al Res ults  
T he res ults of t his trial are e x pecte d t o be p u blis he d i n a peer -re vie we d sci e ntific j o ur nal. 
P u blicati o n of trial res ults will f oll o w Ta ke da p u blicati o n p olicies, a p plica ble i nter nati o nal 
sta n dar ds a n d g ui deli nes f or g o o d p u blicati o n practice, a p plica ble la ws, a n d/ or re g ulati o ns.  
1 5. 5  
I ns ur a nce a n d C o m pe ns ati o n f or I njur y  
Eac h s u bject i n t he trial m ust be i ns ure d i n acc or da nce wit h t he re g ulati o ns a p plica ble t o t he site 
w here t he s u bj ect is parti ci pati n g. If a l ocal u n der writer is re q uir e d, t he n t h e s p o ns or or s p o ns or’s 
desi g nee will o btai n cli nical trial i ns ura nce a gai nst t he ris k of i nj ur y t o cli nical trial s u bjects. Refer 
t o t he Cli nical St u d y Site A gree me nt re gar di n g t h e s p o ns or’s p olic y o n s u bject c o m pe nsati o n a n d 
treat me nt f or i nj ur y. If t h e i n vesti gat or has q uesti o ns re gar di n g t his p olic y, h e or s he s h o ul d c o nt act 
t he s p o ns or or s p o ns or’s desi g nee. 
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1 6. 0  
R E F E R E N C E S  
1.  W orl d Me dical Ass ociati o n Declarati o n of Helsi n ki: et hical pri nci ples f or me dical res earc h 
i n v ol vi n g h u ma n s u bjects. J A M A 2 0 1 3; 3 1 0( 2 0): 2 1 9 1-4.  
2.  I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or P har mace uticals f or 
H u ma n Use (I C H). I C H har m o nise d g ui deli ne. I nte grate d A d d e n d u m t o I C H E 6 ( R 1): 
G ui deli ne f or G o o d Cli nical Practice I C H E 6 ( R 2): I C H C o nse ns us G ui deli ne. A vaila ble at 
htt ps:// w w w.f da. g o v/ me dia/ 9 3 8 8 4/ d o w nl oa d [ Accesse d 0 3 Marc h 2 0 2 1 ]. 
3.  B hatt S, Get hi n g P W, Bra d y OJ, Messi na J P, Farl o w A W, M o yes C L, et al. T he gl o b al 
distri b uti o n a n d b ur de n of de n g ue. Nat ure 2 0 1 3; 4 9 6( 4 4 6): 5 0 4 -7.  
4.  Si m m o ns C P, Farrar JJ, N g u ye n V V C, Wills B. De n g u e. N E n gl J Me d 2 0 1 2; 3 6 6( 1 5): 1 4 2 3 -3 2.  
5.  G u bler DJ. E pi de mic d e n g ue/ d e n g ue he m orr ha gic fe ver as a p u blic healt h, s ocial a n d 
ec o n o mic pr o ble m i n t he 2 1st ce nt ur y. Tre n ds Micr o bi ol 2 0 0 2; 1 0( 2): 1 0 0 -3.  
6.  G uz ma n G M, K o uri G. De n g ue: a n u p date. La n cet I nfect Dis 2 0 0 2; 2( 1): 3 3 -4 2.  
7.  W orl d Healt h Or ga niz ati o n, 2 0 1 9. De n g ue a n d s e v ere de n g u e. Fact S heet. A vaila ble at 
htt ps:// w w w. w h o.i nt/e n/ ne ws -r o o m/fact-s heets/ detail/ de n g u e-a n d -se vere-d e n g ue [ Accesse d 
0 3 Marc h 2 0 2 1 ]. 
8.  W orl d Healt h Or ga niz ati o n, 1 9 9 7. De n g ue he m orr ha gic fe ver: dia g n osis, tr eat me nt, 
pre ve nti o n a n d c o ntr ol, 2 n d E diti o n . Ge ne va. A vaila ble at 
htt p:// w w w. w h o.i nt/csr/res o urces/ p u blicati o ns/ de n g ue/ D e n g ue p u blicati o n/e n/ [ Accesse d 0 3 
Marc h 2 0 2 1 ]. 
9.  W orl d Healt h Or ga niz ati o n, 2 0 0 9. De n g ue g ui deli nes f or dia g n osis, treat me nt, pre ve nti o n a n d 
c o ntr ol. A vaila ble at htt p:// w w w. w h o.i nt /t dr/ p u blicati o ns/ d oc u me nts/ de n g u e-dia g n osis. p df. 
[ Accesse d 0 3  Marc h 2 0 2 1 ]. 
1 0.  Halstea d S, Dee n J. T he f ut ure of de n g u e vacci nes. La n cet 2 0 0 2; 3 6 0( 9 3 4 1): 1 2 4 3 -5.  
1 1.  Wic h ma n n O, Va n nice K, Ast urias EJ, de Al b u q uer q ue L u na EJ, L o n gi ni I, L o pez A L, et al. 
Li ve -atte n uate d t etra v ale nt de n g u e vacci nes: T he nee ds a n d c h alle n ges of p ost -lice ns ure 
e val uati o n of vacci ne s afet y a n d effecti ve n ess. Vacci ne. 2 0 1 7. 3 5( 4 2): 5 5 3 5 -4 2.  
1 2.  Ha di ne g or o S R, Arre d o n d o -García J L, Ca pe di n g M R, Dese da C, C h ot pita yas u n o n d h T, 
Dietz e R,  et al. Efficac y a n d l o n g -t er m safet y of a de n g u e vacci ne i n re gi o ns of e n de mic 
disease. N E n gl J Me d 2 0 1 5; 3 7 3( 1 3): 1 1 9 5 -2 0 6.  
1 3.   Sri d har S, L u e dt ke A, La n ge vi n E, Z h u M, B o na p arte M, Mac ha b ert T, et al. Effect of de n g ue 
ser ostat us o n de n g ue v acci ne safet y a n d efficac y. N E n gl J Me d. 2 0 1 8. 3 7 9( 4): 3 2 7 -4 0.  
1 4.  Re vise d S A G E rec o m me n dati o n o n use of de n g ue vacci ne . A pril 2 0 1 8. A vaila ble at 
htt ps:// w w w. w h o.i nt/i m m u nizati o n/ diseases/ de n g ue/r e vise d _ S A G E _rec o m me n dati o ns _ de n g
ue _ vacci nes _a pr 2 0 1 8/ e n/  [ Accesse d 0 3 Marc h 2 0 2 1].  
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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1 5.  W orl d Healt h Or ga niz ati o n. Wee kl y E pi de mi ol o gical Rec or d. 2 0 1 8. 9 3: 3 2 9 -4 4. A vaila ble at 
htt p:// w w w. w h o.i nt/ wer [ Access e d 0 3  Marc h 2 0 2 1 ]. 
1 6.  Y o ksa n S, B ha mara pra vati N, Halstea d S B. De n g u e vir us vacci ne de v el o p me nt: st u d y o n 
bi ol o gical mar kers of u n cl o ne d de n g ue 1 -4 vir uses seriall y p assa ge d i n pri mar y ki d n e y cells. 
I n: T D St. Ge or ge, B H Ka y a n d J Bl o k (e d.), Ar b o vir us researc h i n A ustralia. Pr ocee di n gs of 
t he 4t h S y m p osi u m. C SI R O/ QI M R, Bris ba ne, A ustralia, 1 9 8 6: 3 5-8.  
1 7.  H ua n g C Y, B utr a pet S, Ts uc hi ya K R, B h a m ara pra vati N, G u bler DJ, Ki n ne y R M. De n g u e  2 
P D K -5 3 vir us as a c hi meric carrier f or tetra vale nt de n g u e vacci ne de vel o p me nt. J. Vir ol 
2 0 0 3; 7 7( 2 1): 1 1 4 3 6 -4 7.  
1 8.  W orl d Healt h Or ga niz ati o n. H u ma n pa pill o ma vir us ( H P V). A vaila ble at 
htt p:// w w w. w h o.i nt/i m m u niz ati o n/ d iseases/ h p v/e n/ [Accesse d 0 3  Marc h 2 0 2 1 ]. 
1 9.  Merc k. G ar dasil 9 prescri bi n g i nf or mati o n. A v aila ble at 
htt ps:// w w w.f da. g o v/ me dia/ 9 0 0 6 4/ d o w nl oa d [ Accesse d 0 3 Marc h 2 0 2 1 ]. 
2 0.  Marc y S M, K o hl K S, Da ga n R, N ali n D, Bl u m M, J o nes M C, et al. Bri g ht o n C olla b orati o n 
Fe ver W or ki n g Gr o u p. Fe ver as a n a d verse e v e nt f oll o wi n g i m m u nizati o n: case defi niti o n a n d 
g ui deli nes of d ata c ollecti o n, a nal ysis a n d prese nt ati o n. Vacci n e 2 0 0 4; 2 2( 5 -6): 5 5 1 -6.  
2 1.  H o wie S R. Bl o o d sa m ple v ol u mes i n c hil d healt h researc h: re vie w of safe li mits. B ull W orl d 
Healt h Or ga n. 2 0 1 1; 8 9: 4 6 -5 3.  
2 2.  P olic y a n d c o m m u nicati o n b ulleti n –  T he cli nical ce nter. G ui deli nes f or li mits of bl o o d dra w n 
f or res earc h p ur p oses i n t he cli nical ce nt er. Ma n u al tra ns mittal s heet, n o. M 9 5-9 (re v.), 2 0 0 9. 
A vaila ble at htt ps://ir b.resear c h. c h o p.e d u/sites/ defa ult/files/ d oc u me nts/ g _ ni h _ bl o o d dra ws. p df 
[ Accesse d 0 3 Marc h 2 0 2 1 ]. 
2 3.  W orl d Healt h Or ga niz ati o n. Re d uci n g p ai n at t he ti me of vacci nati o n: W H O p ositi o n 
pa per -Se pt e m ber 2 0 1 5. W kl y E pi de mi ol Rec 2 0 1 5; 9 0( 3 9): 5 0 5 -1 0.  
 
Pr o p ert y of T a k e d a: F or N o n- C o m m er ci al U s e O nl y a n d S u bj e ct t o t h e A p pli c a bl e T er m s of U s e

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A p pe n di x  A  Res p o nsi bilities of t he I n vesti g at or  
Cli nical researc h st u dies s p o ns ore d b y t he s p o ns or are s u bject t o I C H G C P a n d all t he a p plica ble 
l ocal la ws a n d re g ulati o ns. 
T he i n vesti gat or a grees t o ass u me t he f oll o wi n g res p o nsi bilities:  
1.  C o n d uct t h e trial i n acc or da nce wit h t he pr ot o c ol.  
2.  Pers o nall y c o n d uct or s u per vise t he staff t hat will assist i n t he pr ot oc ol.  
3.  E ns ure t hat trial rel ate d pr oce d ures, i ncl u di n g trial s pecific ( n o n -r o uti ne/ n o n-sta n dar d pa nel) 
scree ni n g ass ess me nts, are N O T perf or me d o n p ote ntial s u bjects pri or t o t he recei pt of writte n 
a p pr o val fr o m rele v a nt g o ver ni n g b o dies/a ut h orities.  
4.  E ns ure t hat all c ollea g u es a n d e m pl o yees assisti n g i n t he c o n d u ct of t he tri al are i nf or me d of 
t hese o bli gati o ns. 
5.  Sec ure pri or a p pr o val of t he trial a n d a n y c ha n ges b y a n a p pr o priate I R B/I E C t hat c o nf or ms t o 
I C H, a n d l ocal r e g ulat or y re q uire me nts. 
6.  E ns ure t hat t he I R B/I E C will be res p o nsi ble f or i nitial re vie w, c o nti n ui n g re vie w, a n d a p pr o val 
of t he pr ot oc ol. Pr o m ptl y re p ort t o t he I R B/I E C all c ha n ges i n researc h acti vit y a n d all 
a ntici pate d ris ks t o s u bjects. Ma ke at least yearl y re p orts o n t he pr o gress of t he trial t o t he 
I R B/I E C, a n d iss ue a fi nal re p ort wit hi n 3 m o nt hs of trial c o m pleti o n. 
7.  E ns ure t hat re q uir e me nts f or i nf or me d c o nse nt/ pe diatric asse nt,  as o utli ne d i n I C H a n d l o cal 
re g ulati o ns, are m et. 
8.  O btai n vali d i nf or me d c o nse nt/ pe diatric asse nt fr o m t he L A R of eac h s u bject/eac h s u bject w h o 
partici pates i n t he trial, a n d d oc u me nt t he date of c o nse nt i n t he s u bject’s me dical c hart. Vali d 
i nf or me d c o nse nt/ pe diatric asse nt f or m is t he m ost c urre nt v ersi o n a p pr o ve d b y t he I R B/I E C. 
Eac h i nf or me d c o nse nt/ p e diatric asse nt f or m s h o ul d c o ntai n a s u bject a ut h orizati o n secti o n 
t hat descri bes t he us es a n d discl os ures of a s u bject’s pers o nal i nf or m ati o n (i ncl u di n g pers o nal 
healt h i nf or mati o n) t hat will ta ke place i n c o n necti o n wit h t he trial. If a n i nf or me d 
c o nse nt/ pe diatric asse nt  f or m d oes n ot i ncl u de s uc h a s u bject a ut h orizati o n, t he n t he 
i n vesti gat or m ust o btai n a se parate s u bject a ut h ori zati o n f or m fr o m eac h su bject or t he 
s u bject’s L A R. 
9.  Pre pare a n d mai ntai n a d e q uate cas e hist ories of all pers o ns e ntere d i nt o t he trial, i ncl u di n g 
e C R Fs, h os pital rec or ds, la b orat or y res ults, etc, a n d mai ntai n t hese data f or a mi ni m u m of 
2  years f oll o wi n g n otificati o n b y t he s p o n s or t hat all i n vesti gati o ns ha ve b ee n disc o nti n ue d or 
t hat t he re g ulat or y a ut h orit y has a p pr o ve d t he mar keti n g a p plicati o n. T he i n vesti gat or s h o ul d 
c o ntact a n d recei ve writt e n a p pr o val fr o m t he s p o ns or bef ore dis p osi n g of a n y s u c h 
d oc u me nts.  
1 0.  All o w p ossi ble  i ns pecti o n a n d c o p yi n g b y t he re g ulat or y a ut h orit y of G C P-s pecifie d esse ntial 
d oc u me nts.  
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1 1.  Mai ntai n c urre nt rec or ds of t he recei pt, a d mi nistrati o n, a n d dis p ositi o n of s p o ns or -s u p plie d 
vacci nes, a n d ret ur n all u n use d s p o ns or -s u p plie d vacci nes t o t he s p o ns or. 
1 2.  Re p ort A Es t o t he s p o ns or pr o m ptl y. I n t he e ve nt of a n S A E, n otif y t he s p o ns or wit hi n 
2 4  h o urs.  
1 3.  Re vie w a n d pr o vi de a si g nat ure as a p pr o val of t h e c o nte nt of t he cli nical st u d y re p ort, if 
re q uire d. 
 
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A p pe n di x  B  I n vesti g at or C o nse nt t o Use of Pers o n al I nf or m ati o n  
Ta ke da will c ollect a n d retai n pers o nal i nf or mati o n of t he i n vesti gat or, i ncl u di n g his or her na me, 
a d dress, a n d ot h er pers o nall y i de ntifia ble i nf or mati o n. I n a d diti o n, i n vesti gat or’s pers o nal 
i nf or mati o n ma y b e tra nsferre d t o ot her parties l oc ate d i n c o u ntries t hr o u g h o ut t he w orl d (e g, t he 
U nite d Ki n g d o m, U S A, a n d J a pa n), i ncl u di n g t he f oll o wi n g:  
•  Ta ke da, its affiliates, a n d lice nsi n g part ners.  
•  B usi ness part n ers assisti n g Ta k e da, its affiliates, a n d lice nsi n g part ners.  
•  Re g ulat or y a ge n cies a n d ot her healt h a ut h orities.  
•  I R Bs a n d I E Cs. 
I n v esti gat or’s pers o nal i nf or mati o n ma y be retai ne d, pr ocesse d, a n d tra nsferre d b y Ta k e da a n d 
t hese ot her parties f or res earc h p ur p oses i ncl u di n g t he f oll o wi n g: 
•  Assess me nt of t he s uita bilit y  of i n vesti gat or f or t h e trial a n d/ or ot her cli nical st u dies.  
•  Ma na ge me nt, m o nit ori n g, i ns pecti o n, a n d a u dit of t he trial.  
•  A nal ysis, re vie w, a n d verificati o n of t he trial res ults.  
•  Safet y re p orti n g a n d p h ar mac o vi gila n ce relati n g t o t he trial.  
•  Pre parati o n a n d  s u b missi o n of re g ulat or y fili n gs, c orres p o n de n ce, a n d c o m m u nicati o ns t o 
re g ulat or y a ge ncies relati n g t o t he trial. 
•  Pre parati o n a n d s u b missi o n of re g ulat or y fili n gs, c orres p o n de n ce, a n d c o m m u nicati o ns t o 
re g ulat or y a ge nci es relati n g t o ot h er v acci n es use d i n ot her cli nical st u dies t h at ma y c o nt ai n t he 
sa me c he mical c o m p o u n d prese nt i n t he i n vesti gati o nal vacci ne. 
•  I ns p ecti o ns a n d i n vesti gati o ns b y re g ulat or y a ut h orities relati n g t o t he tri al. 
•  Self -i ns pecti o n a n d i nter nal a u dit wit hi n Ta ke da, its affiliates, a n d lice nsi n g part ners.  
•  Arc hi vi n g a n d a u dit of tri al rec or ds.  
•  P osti n g i n vesti gat or site c o ntact i nf or mati o n, trial details a n d res ults o n p u blicl y accessi ble 
cli nical trial re gistries, data bases, a n d we bsites.  
I n v esti gat or’s pers o nal i nf or mati o n ma y be transferre d t o ot her c o u ntries t h at d o n ot ha ve data 
pr otecti o n la ws t hat offer t he sa me le vel of pr otecti o n as data pr otecti o n la ws i n i n vesti gat or’s o w n 
c o u ntr y. I n vesti gat or ac k n o wle d ges a n d c o nse nts t o t he use of his or her pers o nal i nf or mati o n b y 
Ta ke da a n d ot her p arties f or t he p ur p oses d escri b e d a b o ve.  
 
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D oc u me nt N u m ber: T A K- 0 0 3- 0 2 9 6 1 v 5. 0
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