A Phase 3, Follow-Up Trial to Evaluate Long-Term Safety and Antibody Persistence, and the Impact of a Booster Dose of a Tetravalent Dengue Vaccine Candidate in Healthy Adolescents and Adults in Areas Non-Endemic for Dengue
Phase: PHASE3
Conditions: Dengue Fever
Sponsor: Takeda

F or n o n- c o m m er ci al u s e o nl y

 
 
 
 
 
 
 
A P h ase 3, F oll o w -U p Tri al  t o E v al u ate L o n g-T er m S afet y a n d A nti b o d y Persiste nce, a n d 
t he I m p act of a B o oster D ose of a Tetr a v ale nt De n g ue V acci ne C a n di d ate i n He alt h y 
A d olesce nts a n d A d ults i n Are as N o n -E n de mic f or De n g ue  
L o n g -T er m S afet y a n d A nti b o d y Persiste nce of T D V a n d t he I m p act of a B o oster D ose 
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 3  
I N D N u m ber:  
0 1 4 2 9 2  
E u dr a C T N u m ber:  
N ot A p plica ble  
Tri al V acci ne 
N a me(s):  
•
I n v esti gati o nal vacci ne: tetra vale nt d e n g ue vacci n e ca n di dat e
( T D V) c o m prise d of a m olec ularl y c h aracterize 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 u e ser ot y p es 2/ 1
rec o m bi na nt strai n ( T D V-1), a de n g u e ser ot y p es 2/ 3
rec o m bi na nt strai n ( T D V-3), a n d a d e n g ue s er ot y p es 2/ 4
rec o m bi na nt strai n ( T D V-4) .
•
Place b o: sali ne s ol uti o n.
T a ke d a A p pr o v al 
D ate:  
2 2 A u g ust 2 0 2 2  
Versi o n:  
Versi o n 5. 0  (s u perse des Versi o n 4 . 0) 
C O N FI D E N T I 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 btai 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 he 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. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
Tri al N o. D E N -3 0 3  
P a ge 2  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
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 
I Q VI A I nte grate d Safet y Ma na ge me nt Lifec ycle Safet y 
E -mail: T a ke da De nsafet y @ Q ui ntiles.c o m
Fa x a n d tele p h o ne n u m bers f or seri o us a d verse e ve nt a n d
pre g na nc y re p orti n g will be pr o vi de d t o t he site.
Me dical M o nit or  
( me dical a d vice o n c o n d uct of pr ot oc ol 
or c o m p o u n d)  
E mer ge nc y me dical c o ntact i nf or mati o n will be pr o vi de d 
t o t he site. 
Res p o nsi ble Me dical Officer  
(carries o verall res p o nsi bilit y f or t he 
c o n d uct of t he trial)  
E mer ge nc y me dical c o ntact i nf or mati o n will be pr o vi de d 
t o t he site. 
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 s u bjects i n acc or da n ce 
wit h t he re q uire me nts of t his cli nical trial pr ot oc ol a n d 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 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 G o o d Cli nical Practice: C o ns oli date d 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.
SI G N A T U R E S  
, M D 
 Cli nical De vel o p me nt 
a n d O perati o ns  
Vacci ne B usi ness U nit  
T a ke d a P har mace uticals I nter nati o nal A G  
Date  
, P h D 
 
Vacci ne B usi ness U nit  
T a ke da P har mace uticals I nter nati o nal A G  
Date  
, P h D 
 P har mac o vi gila nce B e nefit-Ris k  
Vacci ne B usi ness U nit  
T a ke d a P har mace uticals I nter nati o nal A G  
Date  
, M Sc 
 Statistics  
Statistical & Q ua ntitati ve Scie nces  
T a ke da P har mace uticals I nter nati o nal A G  
Date  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 3  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
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 h a ve 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 her pr o d uct i nf or mati o n pr o vi de d  b y t he s p o ns or. I a gree t o c o n d uct t his trial i n 
acc or da nce 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, safet y, pri v ac y, a n d 
well -bei n g of trial s u bjects 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 G o o d Cli nical Prac tice: C o ns oli date d 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 uir e me nts f or re p orti n g s eri o us a d v erse e v e nts defi ne d i n Secti o n  1 0. 1. 5  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 d i x A  –  Res p o nsi bilities of t he I n ve sti 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 nce wit h t he uses c o nte m plate d i n A p pe n di x B  of t hi s 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)  
 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 4  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
1. 3  
Pr ot oc ol V ersi o n 5. 0 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 r efere n ce t o t he pr ot oc ol  ( Versi o n 5 . 0) i nc or p orati n g 
a me n d me nt 3 . 
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 4 Marc h 2 0 1 9  
1. 0  
N ot a p plica ble  
Gl o bal  
0 9  Marc h 2 0 2 0  
3 . 0 
S u bsta ntial  
Gl o bal  
2 2 Fe br uar y 2 0 2 1  
4. 0  
S u bsta ntial  
Gl o bal  
2 2  A u g ust  2 0 2 2  
5. 0  
S u bsta ntial  
Gl o bal  
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 4 . 0, 2 2  Fe br u ar y  2 0 2 1  
R ati o n ale f or t he A me n d me nt:  
T his a me n d me nt o utli nes s u bsta ntial c ha n ges t hat will be i m ple me nte d at i n vesti gati o nal sites 
i n Me xic o t o acc o m m o date a dela y i n t he d eli ver y of t he trial vacci nes t o t he sites i n Me xic o, 
a n d a d mi nistrati ve dela ys d ue t o  t he C O VI D-1 9 p a n de mic . T he b o oster d ose, w hic h was d u e 
t o be a d mi nistere d at 4 5  m o nt hs after t he first va cci nati o n i n t he pri mar y v acci nati o n  series, 
will n o w be a d mi nistere d at 6 3  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n 
series f or s u bjects fr o m p are nt trial D E N-3 1 5 ( Me xic o). All safet y c h ec ks a n d bl o o d dra ws t hat 
were s c he d ule d t o occ ur pri or t o a d mi nistrati o n of t he b o os ter d ose will be c o n d ucte d  as 
pla n ne d , a n d all p ost b o oster  trial pr oce d ures will be a dj uste d acc or di n gl y t o e ns ure t hat a n y 
c ha n ges bei n g ma d e t o t he b o oster sc he d ule d o n ot i m pact s u bject safet y or data i nte grit y. N ote 
t hat t hese c ha n ges o nl y a p pl y t o i n vesti gati o nal sites i n Me xic o , t he y will n ot i m pact sites i n 
t he U nite d States. 
W he n t his a me n d me nt was pre pare d , all s u bjects fr o m pare nt trial D E N-3 0 4 ( U nite d States) 
ha d c o m plete d t heir last trial visit ( Visit 5)  f oll o wi n g b o oster a d mi nistrati o n at Visit 3 
(3 6  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series ). T o per mit t he a nal ysis 
of data c ollecte d at trial sites i n t he U nite d States , an i nteri m a nal ysis (I A) of t he safet y a n d 
i m m u n o ge nicit y data c oll ecte d at trial sites i n t he U nite d States has bee n a d de d . N o 
m o dificati o ns t o t he trial are pla n n e d base d o n t h e res ults of t his  I A. 
Ot her M o dificati o ns  
A d mi nistrati ve trial i nf or mati o n a n d d oc u me nt refere nces ha v e bee n u p d ate d as necess ar y. 
Mi n or st ylistic, gra m matical , a n d e dit orial c ha n ges were i ncl u d e d f or clarifi cati o n p ur p oses 
o nl y.  
D etails of t he c h a n ges t h at ha ve bee n ma de as part of t his a me n d me nt are o utli ne d bel o w. I n 
t his secti o n o nl y, all ne w te xt is s h o w n i n b ol d italics , a n d a n y del ete d  te xt is mar ke d usi n g 
stri ket hr o u g h. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 5  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
Title P a ge  
Pr ot oc ol  
Title P a ge  
Tri al V acci ne N a me(s):  
•  
I n vesti gati o nal vacci ne: tetra vale nt de n g ue vacci ne ca n di dat e ( T D V) 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 c hi meric strai n ( T D V-1), a de n g ue ser ot y pes 2/ 3 rec o m bi na nt c hi mer ic 
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 c hi meric strai n ( T D V-4).  
1. 2  
, M D, P h D 
 Cli nical De vel o p me nt Vacci nes 
, M D 
 Cli nic al Devel o p m e nt a n d O per ati o ns 
V acci ne B usi ness U nit  
T a ke d a P har mace uticals I nter nati o nal A G  
1. 2  
, P h D  
 
V acci ne B usi ness U nit  
T a ke d a P har mace uticals I nter nati o nal A G  
1. 2  
, P h D, M Sc P V 
 P har mac o vi gila nce B e nefit Ris k  
, P h D 
 P h ar m ac o vi gil a nce Be nefit-Ris k  
V acci ne B usi ness U nit  
T a ke d a P har mace uticals I nter nati o nal A G  
1. 2  
, M Sc 
 
Vacci ne Statistics  
, M Sc 
 St atistics 
St atistic al & Q u a ntit ative Sci e nces  
T a ke d a  P har mace uticals I nter nati o nal A G  
2. 0  
Pr o d uct N a me:  
T etra vale nt De n g ue Vacci ne Ca n di date ( T D V)  
T a ke d a’s De n g ue Tetr av ale nt V acci ne ( Live, Atte n u ate d)  ( T D V) 
2. 0  
Bli n di n g Sc he m a:  O pe n u p t o Visit 3 B ( Da y 7 2 0 [ M o nt h 2 4]) f or s u bj ects fr o m pare nt trial 
D E N -3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M o nt h 1 5]) f or s u bj ects fr o m pare nt trial D E N -3 0 4 
( U nite d States) a n d d o u ble -bli n d t hereafter u ntil t he e n d of t he trial  
2. 0  
B ac k gr o u n d a n d R ati o n ale:  
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 r i b o n uclei c aci d 
vir us t hat occ urs as 4 rec o g niz e d ser ot y pes, de n g ue vir us ser oty pe -1, -2, -3, a n d -4 ( D E N V -1, 
D E N V -2, D E N V -3, or a n d  D E N V -4 ). 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 6  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
2. 0  
B ac k gr o u n d a n d R ati o n ale:...  
A first tetra vale ntrec o m bi n a nt de n g ue vacci ne (c hi meric yell o w fe ver vir us de n g ue vir us -
tetra vale nt d e n g ue vacci ne [ C Y D-T D V]) was a p pr o ve d i n s o me c o u ntries i n As ia a n d Lati n 
A merica i n 2 0 1 5, i n E ur o pe i n 2 0 1 8, a n d i n t he U nite d States i n 2 0 1 9 . I nitial fi n di n gs s h o we d 
t hat vacci ne efficac y was differe nt bet 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. F urt her a nal ys es s h o we d t hat pe o ple w h o ha d n ot bee 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 if t he y were i nfecte d after vacci nati o n 
wit h C Y D -T D V. I n a revise d Str ate gic A dvis ory Gr o u p of E x perts o n I m m u niz ati o n ( S A G E) 
rec o m m e n d ati o n i n A pril 2 0 1 8, t he S A G E co ncl u de d t h at f or c o u ntries c o nsi deri n g 
C Y D -T D V v a cci n ati o n as p art of t heir de n g ue c o ntr ol pr o gr a m, a “ pre -v acci n ati o n scree ni n g 
str ate gy ” w o ul d be t he preferre d o pti o n, i n w hic h o nly de n g ue -ser o p ositive pers o ns are 
v a cci n ate 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 effica ci o us 
de n g ue vacci nes.  
T a ke d a’s De n g ue Tetr a v ale nt De n g ue V acci ne C a n di d ate ( Live, Atte n u ate d) ( T D V) - 
B ac k gr o u n d:  
T a ke d a’s T D V  c o nsists of 1 m olec ularl y c haracterize d, atte n uate d de n g ue ser ot y pe 2 vir us strai n 
a n d 3 rec o m bi na nt c hi meric 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 
de n g ue ser ot y pes  1 4  1, 3, a n d 4 . T he de n g ue ser ot y pe 2 str ai n ( T D V -2) is base d u p o n t he 
atte n uate d la b orat or y -deri ve d vir us D E N V -2 vir us strai n, ori gi nall y is olate d at Ma hi d ol 
U ni versit y, B a 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  c hi meric , 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 D V -2 wit h t he pr M a n d E ge nes fr o m 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, res pecti vel y. T h us, T a ke da’s T D V  is c o m prise d of 4 
de n g ue vir us strai ns: T D V -2 ( a m olec ularl y c haracterize d atte n uate d de n g ue ser ot y pe 2 str ai n) 
( T D V-2) , a de n g ue ser ot y pes 2/ 1 rec o m bi na nt c hi meric strai n ( T D V-1), a de n g ue ser ot y pes 
2/ 3  rec o m bi na nt c hi meric 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 c hi meri c 
strai n ( T D V-4).  
N o ncli nical st u dies carrie d o ut i n mice a n d n o n h u ma n pri mat es ha ve de m o nstrate d a n acce pta ble 
safet y, i m m u n o ge nicit y, a n d efficac y pr ofile f or T a ke da’s T D V . A d diti o nall y, dD ata 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 nicit y, 
safet y a n d i m m u n o ge nicit y pr ofiles f or T a ke da’s T D V  i n he alt h y a d ults i n n o n-e n de mic ar eas 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 As ia a n d Lati n A merica. O n g oi n g a n d 
cC o m plete d p hase 2 cli nical trials ha ve e na ble d t he selecti o n of a fi nal T D V  d ose (i n a 
l y o p hilize d f or m ulati o n) a n d a t w o2 -d ose vacci nati o n series 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 cli nic al devel o p m e nt  
pr o gra m. I n J a n uar y 2 0 1 9,Res ults fr o m  t he pi v otal D E N-3 0 1 efficac y trial s h o we d t h at t h e met 
its pri mar y e n d p oi nt w as m et, de m o nstrati n g t hat T D V was efficaci o us i n pre ve nti n g de n g ue 
fe ver i n c hil dre n a n d a d olesce nts li vi n g i n de n g ue-e n de mic c o u ntries. T D V h as bee n give n t o 
> 2 0, 0 0 0 cli nic al tri al s u bjects. All a vaila ble data als o s h o we d t hat T D V was well t olera te d wit h 
n o si g nifica nt safet y c o ncer ns t o date.  
2. 0  
R ati o n ale f or t he Pr o p ose d Tri al:...  
S u bj ects pre vi o usl y e nr olle d i n t w o pare nt trials ( D E N -3 0 4 a n d D E N -3 1 5) will i nitiall y be 
i n vite d t o partici pate i n t he D E N-3 0 3 f oll o w -u p trial fr o m 2 1 m o nt hs after t he first vacci nati o n 
i n t he pri mar y vacci nati o n seri es i n t he pare nt trials. T he i ncl usi o n of s u bj ects fr o m ot her trials 
wit hi n t he T D V pr o gra m ma y als o be c o nsi d ere d if t he y meet t he eli gi bilit y criteria f or e ntr y 
i nt o D E N 3 0 3. A nti b o d y persiste nce will be assesse d i n all s u bj ects f or u p t o 4 5 6 3  m o nt hs after 
t he first vacci nati o n i n t he pri mar y vacci nati o n series f or s u bj ects fr o m pare nt trial D E N-3 1 5 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 7  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
( Me xic o) a n d f or u p t o 3 6 m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n seri es f or 
s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States).  
2. 0  
Tri al Desi g n:...  
T he i ncl usi o n of s u bj ects fr o m ot her trials wit hi n t he T D V pr o gra m ma y be c o nsi dere d if t he y 
meet t he eli gi bilit y criteria f or e ntr y i nt o D E N -3 0 3. D E N -3 0 3 will i ncl u de u p t o 6 0 0 healt h y 
s u bj ects a ge d ≥1 3 t o ≤6 3 years at trial e ntr y. T o e na ble t he assess me nt of a b o oster d ose, t he trial 
will b e d o u ble -bli n de d, ra n d o mize d, a n d place b o -c o ntr olle d fr o m Visit 3 B ( Da y 7 2 0 [ M 2 4])  
o n war ds  f or s u bj ects fr o m par e nt trial D E N-3 1 5 ( Me xic o ) a n d fr o m Visit 3 ( Da y 4 5 0 [ M 1 5]) 
o n war ds f or s u bj ects fr o m par e nt trial D E N -3 0 4 ( U nite d States) . 
A nti b o d y persiste nce a n d safet y will be assesse d fr o m Visit 1 ( Da y 1 [ M 0]) t hr o u g h Visit 3B  
(Da y  7 2 0 [ M 2 4]) f or u p t o 4 5 6 3  m o nt hs after t he first vacci nati o n  i n t he pri mar y vacci nati o n 
series f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o) a n d fr o m Visit 1 ( Da y 1 [ M 0]) t hr o u g h 
Visit 3 ( Da y  4 5 0 [ M 1 5]) f or u p t o 3 6 m o nt hs after t he first vacci nati o n i n t he pri mar y 
vacci nati o n series f or s u bj ects fr o m pare nt tria l D E N-3 0 4 ( U nite d States). F urt her 
c haracterizati o n of t he l o n g -ter m h u m oral a n d cell-me diate d i m m u ne res p o nses t o T a ke da’s 
T D V will be u n derta ke n i n a s u bset of a p pr o xi matel y 5 0 v ol u nteers i de ntifie d at e nr oll me nt 
(cell-me diate d i m m u nit y [ C MI] s u bset: par tici pati o n is o n a v ol u ntar y basis fr o m D E N-3 0 4 o nl y) 
u p t o Visit 5  ( Da y 6 3 0 [ M 2 1]) . A rete nti o n p h o ne call will b e ma de bet wee n Visits 1 a n d 2 o n 
Da y 1 8 0 ( M 6) t o mai ntai n c o ntact wit h t he s u bj ect/t he s u bj ect’s le gall y acce pta ble re prese ntati ve 
( L A R) bet wee n site visits a n d t o re mi n d t he s u bj ect/t he s u bj ect’s L A R of a n y u pc o mi n g sit e 
visits. At Visit 3 A ( Da y 4 5 0 [ M 1 5])  f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 2 
( Da y 3 6 0 [ M 1 2]) f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States),  t he site will disc uss 
a n y i nf or mati o n t hat is perti ne nt t o t he b o oster p hase of t he trial wit h t he s u bj ect. A sec o n d 
rete nti o n p h o ne c all will be m a de t o s u bjects fr o m p are nt tri al D E N -3 1 5 ( Me xic o) bet wee n 
Visits 2 a n d 3 o n D ay 5 4 0 ( M 1 8).  D ue t o c ha n ges i n t he trial desi g n i n Me xic o (pr ot oc ol 
a me n d me nt 1, date d 0 9 Marc h 2 0 2 0 a n d pr ot oc ol a me n d me nt 2, date d 2 2 Fe br uar y 2 0 2 1 pr ot oc ol 
a m e n d m e nt 3, d ate d 2 2 A u g ust  2 0 2 2 ), all s u bj ects fr o m p are nt tri al D E N-3 1 5  ( Me xic o) will 
als o n o w be as ke d t o re -c o nse nt usi n g an  u p date d i nf or me d c o nse nt f or m  (I C F)(s) or a n u p date d 
i nf or me d c o nse nt a n d pe diatric asse nt f or ms, as a p plic a ble, at Visit  2 ( Da y 3 6 0 [ M 1 2]) Visit 3  or 
at t he ne xt site visit if Visit 2 has passe d  bef ore a n y f urt her pr ot oc ol -directe d pr oce d ures are 
perf or me d. A n  oral s u m mar y of a n y maj or c ha n ges t hat ha ve bee n ma de t o t he st u d y will be 
pr o vi de d t o t he s u bj ect a n d s u bj ect’s L A R w here a p plica ble i n a d diti o n t o t he I C F/ Asse nt F or m; 
t his will be d oc u me nte d i n t he me dical c hart as part of t he re-c o nse nt pr ocess . Re-c o nse nt date 
s h o ul d als o be d oc u me nte d i n t he electr o nic Case Re p ort F or m (e C R F). A n a d diti o nal rete nti o n 
p h o ne call will be ma d e t o s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o) bet wee n Visit 3 A a n d 
Visit 3 B o n Da y 6 3 0 ( M 2 1) t o mai ntai n c o ntact wit h t h e s u bj ect/t he s u bj ect’s L A R bet wee n site 
visits, a n d t o re mi n d t he s u bj ect/t he s u bj ect’s L A R of t he b o oster eli gi bilit y criteria a n d t he 
u pc o mi n g site visit. Fe male s u bj ects of c hil d beari n g a ge will als o be re mi n de d of pre g na nc y 
a v oi da nce g ui da nce a n d acce pta ble met h o ds of c o ntrace pti o n d uri n g t his call.  
At Visit 3 B ( Da y 7 2 0 [ M 2 4 ]) f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3  ( Da y 4 5 0 
[ M 1 5]) f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d Stat es) , f oll o wi n g all sc he d ule d bl o o d 
dra ws, all s u bj ects will be scree ne d f or ‘ b o oster eli gi bilit y’ t o deter mi ne if t he y are eli gi bl e t o g o 
o n t o recei ve t he T D V b o oster i n t he b o oster p hase. A n y s u bj ect w h o fails t o meet t he criteria f or 
‘ b o oster eli gi bilit y’ will e n d t he trial at Visit 3B  (Da y 7 2 0 [ M 2 4])/ Visit  3 ( Da y 4 5 0 [ M 1 5]), 
res pecti vel y. All eli gi ble s u bj ects will be ra n d o mize d, usi n g a n i nteracti ve res p o nse tec h n ol o g y 
at Visit 3 B ( Da y 7 2 0 [ M 2 4]))/ Visit 3 ( Da y 4 5 0 [ M 1 5]), as a p plica ble, t o 1 of 2 trial gr o u ps 
( Gr o u p 1 a n d Gr o u p 2) i n a 1: 1 rati o stratifie d b y pare nt trial a n d ser ostat us at baseli ne i n t he 
pare nt trials. S u bj ects all ocate d t o Gr o u p 1 will recei ve t he T D V b o oster (si n gle d ose) a n d 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 8  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
s u bj ects all ocate d t o Gr o u p 2 will recei ve place b o. T he i m p act of t he T D V b o oster o n 
ne utralizi n g a nti b o d y titers  a n d ser o p ositi vit y rates will be assesse d at 1 m o nt h a n d 6 m o nt hs 
after a d mi nistrati o n of t he T D V b o oster or place b o. Safet y assess me nts will c o nti n ue f or 6 
m o nt hs f oll o wi n g T D V b o oster or place b o a d mi nistrati o n f or s u bj ects i n Gr o u ps 1 a n d 2.  
F or s u bj ect s fr o m pare nt trial D E N-3 1 5 ( Me xic o), t he d urati o n of t he c urre nt trial will be 2 4 4 2  
m o nt hs f or s u bj ects w h o fail t o meet t he criteria f or ‘ b o oster eli gi bilit y’ at Visit 3 B  a n d 3 0 4 8  
m o nt hs f or all ot her s u bj ects. F or s u bj ects fr o m pare nt trial D E N -3 0 4 ( U ni te d States), t he 
d urati o n of t he c urre nt trial will be 1 5 m o nt hs f or s u bj ects w h o fail t o meet t he criteria f or 
‘ b o oster eli gi bilit y’ at Visit 3 ( Da y 4 5 0 [ M 1 5]) a n d 2 1 m o nt hs f or all ot her s u bj ects. A sc he matic 
of t he trial desi g n is prese nte d bel o w i n Fi g ure 1.  
2. 0  a n d 6. 1  
T he tri al d esi g n sc h e m atic h as bee n u p d ate d t o refl ect t he f oll o wi n g c h a n ges t o t he st u dy desi g n 
i n Mexic o: mer gi n g of Visit 3 A a n d Visit 3 B a n d del aye d  b o oster a d mi nistr ati o n.  
 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 9  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
  
N ote t hat t he ti mi n g of Visit 1, Visit 2, a n d Visit 3 A/ 3  will be t he sa me f or all s u bjects ( Da y  1  [ M 0], Da y 
3 6 0 [ M 1 2], a n d Da y 4 5 0 [ M 1 5], res pecti vel y), b ut f or o perati o nal reas o ns, a d mi nistrati o n of t h e b o oster 
d ose will be dela ye d u ntil Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bjects fr o m pare nt trial D E N 3 1 5 ( Me xic o). I n 
s u bjects w h o recei ve t h e T D V b o oster or place b o, Visit 4 a n d Vi sit 5 will occ ur at 1 m o nt h a n d 6 m o nt hs 
p ost b o oster, res pecti vel y: D a y 7 5 0 ( M 2 5) a n d Da y 9 0 0 ( M 3 0) f or s u bjects fr o m pare nt trial D E N 3 1 5 
( Me xic o)/ Da y 4 8 0 ( M 1 6) a n d Da y 6 3 0 ( M 2 1) f or s u bjects fr o m pare nt trial D E N-3 0 4 ( U nite d States). F or 
all s u bjects, V isit 1, Visit 2, a n d Visit 3 A/ 3 c orres p o n d t o 2 1 m o nt hs, 3 3 m o nt hs, a n d 3 6 m o nt hs after t he 
first va cci n ati o n i n t he pri mar y va cci n ati o n series, res pecti vel y. F or s u bjects fr o m pare nt trial D E N 3 1 5 
( Me xic o), Visit 3 B, Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 4 5 m o nt hs, 4 6 m o nt hs a n d 5 1 m o nt hs 
after t he first vacci n ati o n i n t h e pri mar y va cci n ati o n series, res pecti vel y. F or s u bjects fr o m pare nt trial 
D E N 3 0 4 ( U nite d States), Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 3 7 m o nt hs a n d 4 2 m o nt hs afte r t h e 
first va cci n ati o n i n t he pri mar y va cci n ati o n series, res pecti vel y. 
F or all s u bjects, Visit 1  a n d Visit 2  c orres p o n d t o 2 1 m o nt hs  a n d  3 3 m o nt hs after t he first v acci n ati o n i n 
t he pri m ary v acci n ati o n series i n t he p are nt tri al. F or s u bjects fr o m p are nt tri al D E N-3 1 5 ( Me xic o), Visit 
3, Visit 4, a n d Visit 5 i n t his tri al c orres p o n d t o 6 3 m o nt hs, 6 4 m o nt hs, a n d 6 9 m o nt hs after t he first 
v acci n ati o n i n t he pri m ary v acci n ati o n series, res pectively. F or s u bjects fr o m p are nt tri al D E N -3 0 4 
( U nite d St ates), Visit 3, Visit 4, a n d Visit 5 i n t his tri al c orres p o n d t o 3 6 m o nt hs, 3 7 m o nt hs, a n d 4 2 
m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series, res pectively.  
*  D ue t o c ha n ges i n t he trial desi g n i n Me xic o (pr ot o c ol a me n d me nt 1, date d 0 9 Marc h 2 0 2 0  a n d pr ot oc ol 
a me n d me nt 2, date d 2 2 Fe br uar y 2 0 2 1 pr ot o c ol a m e n d m e nt 3, d ate d 2 2  A u g ust  2 0 2 2 ), all s u bjects fr o m 
p are nt tri al D E N -3 1 5  ( Me xic o) will als o n o w be as ke d t o re -c o nse nt usi n g a n  u p date d i nf or me d c o nse nt 
f or m(s) (I C F) or a n u p date d i nf or me d c o nse nt a n d pe diatric asse nt f or m s, as a p plic a ble,  at Visit 3  Visit 2 
( Da y 3 6 0 [ M 1 2]) or at t h e ne xt site visit if Visit 2 has p asse d bef ore a n y f urt h er pr ot o c ol -directe d 
pr oce d ures are perf or me d. A n  oral s u m mar y of a n y maj or c ha n ges t hat ha ve bee n ma de t o  t h e st u d y will be 
pr o vi d e d t o t h e s u bject a n d s u bject’s L A R w here a p plica ble i n a d diti o n t o t he I C F/ Asse nt F or m; t his will 
be d oc u me nte d i n t he me dical c hart as p art of t h e re -c o nse nt pr ocess. Re -c o nse nt date s h o ul d als o be 
d oc u me nte d i n t h e e C R F.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 0  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
2. 0  
I m m u n o ge nicit y e v al u ati o n: 
•  
Ne utralizi n g a nti b o dies ( b y mi cr o ne utralizati o n test 5 0 % [ M N T 5 0]) will be meas ure d usi n g 
bl o o d sa m ples c ollecte d fr o m all s u bj ects at Visit 1, Visit 2, a n d Visit 3 A/ 3, at Visit 3 B f or 
s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o) , a n d als o at Visit 4 a n d Visit 5 f or s u bj ects w h o 
are ra n d o mize d t o Gr o u ps 1 a n d  2.  
•  
At Visit 3 A/ 3, a lar ger v ol u me of bl o o d will be c ollecte d fr o m all s u bj ects  t o assess 
e x pl orat or y mar kers of t he l o n g -ter m h u m oral i m m u ne res p o nse t o T a ke da’s T D V. 
2. 0  
S afet y e v al u ati o n:  
Diar y car ds will be distri b ute d t o Gr o u ps 1 a n d 2 at Visit 3 B f or s u bj ects fr o m pare nt trial D E N
3 1 5 ( Me xic o)/ Visit 3 f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States) f or t he rec or di n g of: 
2. 0  
S afet y e v al u ati o n :... 
•  
Me dicall y atte n de d A Es ( M A A Es) will be c ollecte d, f or Gr o u ps 1 a n d 2, f oll o wi n g 
a d mi nistrati o n of t he T D V b o oster or place b o fr o m Visit 3 B  t hr o u g h Visit 5 f or s u bj ects 
fr o m pare nt trial D E N-3 1 5 ( Me xic o)/fr o m Visit 3 t hr o u g h Visit 5 f or s u bj ects fr o m pare nt 
trial D E N 3 0 4 ( U nite d States) . M A A Es are defi ne d as A Es l ea di n g t o a n u nsc he d ule d visit 
t o or b y a healt hcare pr ofessi o nal i ncl u di n g visits t o a n e mer ge nc y de p art me nt, b ut n ot 
f ulfilli n g seri o us ness criteria. 
2. 0  
Pri m ar y O bjecti ves:  
•  
T o descri be a nti b o d y persiste nce f or eac h of t he 4 de n g ue ser ot y pes f or u p t o 4 5 6 3  m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series f or s u bj ects fr o m pare nt trial 
D E N -3 1 5 ( Me xic o) a n d f or u p t o 3 6 m o nt hs after t he first va cci nati o n i n t he pri mar y 
vacci nati o n series f or s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nite d State s). 
•  
T o descri be t he i m pact of a T D V b o oster d ose vs place b o o n a nti b o d y res p o nse f or eac h of 
t he 4 de n g ue ser ot y pes at 1 m o nt h a n d 6 m o nt hs p ost a d mi nistrati o n of t he T D V b o oster or 
place b o . 
N ote t hat t he ti mi n g of Visit 1, Visit 2, a n d Visit 3 A/ 3  will b e t he sa me f or all s u bj ects 
( Da y 1  [ M 0], Da y 3 6 0 [ M 1 2], a n d Da y 4 5 0 [ M 1 5], res pecti vel y), b ut f or o perati o nal reas o ns, 
a d mi nistrati o n of t he b o oster d ose will be dela ye d u ntil Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects 
fr o m pare nt trial D E N 3 1 5 ( Me xic o). I n s u bj e cts w h o recei ve t he T D V b o oster or place b o, Visit 
4 a n d Visit 5 will occ ur at 1 m o nt h a n d 6 m o nt hs p ost b o oster, res pecti vel y: Da y 7 5 0 ( M 2 5) a n d 
Da y 9 0 0 ( M 3 0) f or s u bj ects fr o m pare nt trial D E N
3 1 5 ( Me xic o)/ Da y 4 8 0 ( M 1 6) a n d Da y 6 3 0 
( M 2 1) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States). F or all s u bj ects, Visit 1, Visit 2, 
a n d Visit 3 A/ 3  c orres p o n d t o 2 1 m o nt hs, 3 3 m o nt hs, a n d 3 6 m o nt hs after t he first vacci nati o n i n 
t he pri mar y vacci nati o n series, res pecti vel y. F or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o), 
Visit 3 B, Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 4 5 m o nt hs, 4 6 m o nt hs a n d 5 1 m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series, r es pecti vel y. F or s u bj ects fr o m pare nt 
trial D E N-3 0 4 ( U nite d States), Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 3 7 m o nt hs a n d 4 2 
m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series, res pecti vel y.  
2. 0  
Sec o n d ar y O bjecti ves:  
I m m u n o ge nicity 
A nti b o d y P ersiste nce  
•  
T o descri be t he o verall tre n d i n a nti b o d y deca y f or all 4 de n g ue ser ot y pes fr o m val ues 
o btai ne d after t he pri mar y vac ci nati o n series i n t he pare nt tri als t hr o u g h 4 5 6 3  m o nt hs after 
t he first vacci nati o n i n t he pri mar y vacci nati o n series f or s u bj ects fr o m pare nt trial 
D E N -3 1 5  ( Me xic o) a n d t hr o u g h 3 6 m o nt hs after t he first va cci nati o n i n t he pri mar y 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 1  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
vacci nati o n series f or s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nite d States).  
I m pact of a T D V B o oster D ose 
•  
T o descri be t he i m pact of a T D V b o oster o n a nti b o d y res p o nse f or eac h of t he 4 de n g ue 
ser ot y pes f or u p t o 5 1 6 9  m o nt hs f oll o wi n g t he first vacci nati o n i n t he pri mar y vacci nati o n 
series f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o) a n d f or u p t o 4 2  m o nt hs f oll o wi n g 
t he first vacci nati o n i n t he pri mar y vacci nati o n series f or s u bj ects fr o m pare nt trial 
D E N -3 0 4  ( U nite d States). 
S afety  
•  
T o descri be t he l o n g -ter m safet y of T a ke da’s T D V f or u p t o 4 5 6 3 m o nt hs i n pre vi o usl y 
vacci nate d s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o) a n d f or u p t o 3 6 m o nt hs i n 
pre vi o usl y vacci nate d s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nite d States).  
2. 0  
E x pl or at or y O bjecti ves:  
A p plic a ble t o s u b jects fr o m p are nt tri al D E N-3 1 5 ( Me xic o o nly):  
•  
T o e val uate as pects of t he l o n g -ter m h u m oral i m m u ne res p o nse t o T a ke da’s T D V i n all 
s u bj ects at 3 6 6 3  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he 
pare nt trial  ( D E N-3 1 5) s a n d i n t he C MI s u bset (a p plica ble t o s u bj ects fr o m pare nt trial 
D E N 3 0 4 [ U nite d States] o nl y) at 1 m o nt h a n d 6 m o nt hs p ost b o oster i n t he c urre nt trial ; 
t his is i ncl usi ve of, b ut n ot restricte d t o, a n assess me nt of t he a nti-de n g ue N o n -Str uct ural 
pr otei n 1 ( N S 1) a nti b o d y res p o nse.  
A p plica ble t o s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nite d St ates o nl y):  
•  
T o ev al u ate as pects of t he l o n g -ter m h u m or al i m m u ne res p o nse t o T a ke d a’s T D V i n all 
s u bjects at 3 6 m o nt hs after t h e first v acci n ati o n i n t he pri m ary v a cci n ati o n series i n t he 
p are nt tri al  ( D E N-3 0 4) , a n d i n t he C MI s u bset at 1 m o nt h a n d 6 m o nt hs p ost b o oster i n 
t he c urre nt tri al; t his is i ncl usive of, b ut n ot restricte d t o, a n assess m e nt of t he a nti-
de n g ue N S 1 a nti b o dy res p o nse.  
•  
T o e val uate as pects of t he l o n g -ter m cell -me diate d i m m u ne res p o nse t o T a ke da’s T D V u p t o 
3 6 m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trial 
( D E N-3 0 4)  a n d at 1 m o nt h a n d 6 m o nt hs p ost b o oster i n t he c urre nt trial; t his is i ncl usi ve of, 
b ut n ot restrict e d t o, t he ma g nit u de (I nterfer o n -ga m ma E nz y me -Li n ke d I m m u n os p ot [I F N -γ 
E LI S p ot]) of t he l o n g -ter m T cell-me diate d i m m u ne res p o ns e t o T D V ( C MI s u bset o nl y).  
2. 0  
S u b ject P o p ul ati o n:... 
Pla n ne d N u m ber of Trial Ar ms: A si n gle o pe n ar m u p t o Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects 
fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial 
D E N 3 0 4 ( U nite d States)  a n d t w o ar ms t hereafter t hr o u g h t h e e n d of trial, ra n d o mize d i n a 1: 1 
rati o stratifie d b y pare nt trial a n d ser ostat us at baseli ne i n t he pare nt trials 
2. 0  
E xcl usi o n Criteri a at E ntr y:...  
4.    S u bj ects wit h a pr ol o n ge d peri o d  of ha bitati o n ( ≥1 year) i n a de n g ue e n de mic area wit hi n t he 
2 years pri or t o Visit 1  ( Da y 1[ M 0]). 
2. 0  
B o oster Eli gi bilit y:  
Assesse d at Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o) a n d 
Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N
3 0 4 ( U nite d States). A n y s u bj ect 
w h o meets a n y of t he f oll o wi n g criteria at Visit 3 will n ot q ualif y f or ra n d o mizati o n t o Gr o u p 1 
or 2 t o recei ve t he T D V b o oster or place b o, res pecti vel y:  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 2  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
2. 0  
B o oster Eli gi bilit y:...  
5.  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 Visit 3 B ( Da y 7 2 0 
[ M 2 4]) f or s u bj ects fr o m pare nt trial D EN -3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or 
s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States) ; use of i n hale d, i ntra nasal, or 
t o pical c ortic oster oi ds is 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 we i g ht/ da y pre d nis o ne ≥2 wee ks) wit hi n 6 0 da ys pri or t o 
Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o)/ Visit 3 
( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States) . 
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 a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or 
s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects 
fr o m pare nt trial D E N-3 0 4 ( U nite d States) ; 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.  
d)  Recei pt of i m m u n osti m ula nts wit hi n 6 0 da ys pri or t o Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or 
s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects 
fr o m pare nt trial D E N-3 0 4 ( U nit e d States) . 
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 Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N -
3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m par e nt trial D E N -3 0 4 ( U n ite d 
States) . 
2. 0  
B o oster Eli gi bilit y:...  
1 3.  Fe male s u bj ects of c hil d -beari n g p ote ntial 1 w h o are se x uall y acti ve wit h me n, 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 Visit 3 B 
( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) 
f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States) . 
1 4.  Fe male s u bj ects of c hil d beari n g p ote ntial w h o are se x uall y a cti 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” f or u p t o 6 wee ks after a d mi nistrati o n of t he 
T D V  b o oster or place b o at Visit 3 B ( Da y  7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N
3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u b j ects fr o m par e nt trial D E N 3 0 4 ( U nite d 
States) . 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 or breastfee d d uri n g t his peri o d. 
C orres p o n di n g f o ot n ote:  
2 H or m o nal c o ntrace pti ves (e g, oral, i nj ecti o n, tra ns der mal patc h, i m pla nt, cer vical ri n g), barrier 
met h o d (c o n d o m wit h s per mici de or dia p hra g m wit h s per mici de) e ver y ti me d uri n g i nterc o urse, 
i ntra uteri ne de vice, m o n o ga m o us relati o ns hi p wit h a vasect o mize d part ner ( part ner m ust ha ve 
bee n vasect o mize d f or at least si x6  m o nt hs pri or t o Visit  3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m 
pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 
( U nite d States). Ot her c o ntrac e pti ve met ho ds ma y be c o nsi d ere d i n a gree me nt wit h t he s p o ns or 
a n d m ust b e a p pr o ve d b y t he a p pr o priate et hics c o m mittee . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 3  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
2. 0  
Tri al V acci ne a n d Pl ace b o:  
I nvesti g ati o n al v acci ne  
T he i n vesti gati o nal vacci ne is T a ke da’s T D V , a tetra vale nt vacci ne c o m prise d of 1 m olec ul arl y 
c haracterize d, atte n uate d de n g ue vir us strai n ( T D V -2), a n d 3 rec o m bi na nt c hi meric de n g ue vir us 
strai ns 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 g1 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.  
2. 0  
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 e ac h s u bj ect will be bet wee n 2 4 4 2  m o nt hs a n d 3 0 4 8  m o nt hs f or s u bj ects 
fr o m pare nt trial D E N-3 1 5 ( Me xic o), a n d bet wee n 1 5 m o nt hs a n d 2 1 m o nt hs f or s u bj ects fr o m 
pare nt trial D E N -3 0 4 ( U nite d States) . 
2. 0  
Criteri a f or E v al u ati o n a n d A n al yses:  
N ote, f or all s u bjects Visit 1 ( D ay 1 [ M 0]) a n d Visit 2 ( D ay 3 6 0 [ M 1 2]) c orres p o n d t o 
2 1  m o nt hs a n d 3 3 m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series i n t he 
p are nt tri al. F or s u bjects fr o m p are nt tri al D E N -3 1 5 ( Me xic o), Visit 3 ( D ay 1 2 6 0 [ M 4 2]), Visit 
4 ( D ay 1 2 9 0 [ M 4 3]), a n d Visit 5 ( D ay 1 4 4 0 [ M 4 8 ]) i n t his tri al c orres p o n d t o 6 3 m o nt hs, 6 4 
m o nt hs, a n d 6 9  m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series, 
res pectively. F or s u bjects fr o m p are nt tri al D E N-3 0 4 ( U nite d St ates), Visit 3 ( D ay 4 5 0 [ M 1 5]), 
Visit 4 ( D ay 4 8 0 [ M 1 6]), a n d Visit 5 ( D ay 6 3 0 [ M 2 1]) i n t his tri al c orres p o n d t o 3 6 m o nt hs, 
3 7  m o nt hs, a n d 4 2 m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series i n t he 
p are nt tri al, res pectively.  
Pri m ar y e n d p oi nts:  
•  
Ge o metric mea n titers ( 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 a n d ser o p ositi vit y rates ( % of s u bj ects wit h reci pr ocal ne utralizi n g titer 
≥1 0) f or eac h of t he 4 de n g ue ser ot y pes a n d m ulti ple ( 2, 3 or 4) at Visit 1  ( Da y 1 [ M 0]), 
Visit  2  ( Da y 3 6 0 [ M 1 2]), a n d Visit 3 A ( Da y 4 5 0 [ M 1 5]), a n d Visit 3 B ( Da y 7 2 0 [ M 2 4] ; 
(pri or t o a d mi nistrati o n of t he T D V b o oster or place b o f or s u bj ects ra n d o mize d t o Gr o u ps 1 
a n d 2, res pecti vel y)  f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o) a n d at Visit 1 ( Da y 1 
[ M 0]), Visit 2 ( Da y 3 6 0 [ M 1 2]), a n d Visit 3 ( Da y 4 5 0 [ M 1 5]; pri or t o a d mi nistrati o n of t he 
T D V b o oster or place b o f or s u bj ects ra n d o mize d  t o Gr o u ps 1 a n d 2, res pecti vel y) f or 
s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States),  s u m marize d f or all s u bj ects, f or all 
s u bj ects b y pare nt trial, a n d f or all s u bj ects b y ser ostat us at baseli ne i n t he pare nt trials.  
•  
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 a n d 
ser o p ositi vit y rates ( % of s u bj ects wit h reci pr ocal ne utralizi n g titer ≥1 0) f or eac h of t he 4 
de n g ue ser ot y pes a n d m ulti ple ( 2,  3  or 4) at Visit 4  ( Da y 7 5 0 [ M 2 5] f or s u bj ects fr o m pare nt 
trial D E N-3 1 5 [ Me xic o ]/ Da y 4 8 0 [ M 1 6] f or s u bj ects fr o m pare nt trial D E N-3 0 4 [ U nite d 
States])  a n d Visit 5  ( Da y 9 0 0 [ M 3 0] f or s u bj ects fr o m pare nt trial D E N-3 1 5 
[ Me xic o]/ Da y 6 3 0 [ M 2 1] f or s u bj ects fr o m pare nt trial D E N -3 0 4 [ U nite d States]),  f or 
s u bj ects ra n d o mize d t o Gr o u ps 1 a nd 2 b y trial gr o u p, b y tri al gr o u p a n d pare nt trial, a n d b y 
trial gr o u p a n d ser ostat us at baseli ne i n t he pare nt trials. 
N ote t hat t he ti mi n g of Visit 1, Visit 2, a n d Visit 3 A/ 3  will b e t he sa me f or all s u bj ects 
( Da y 1  [ M 0], Da y 3 6 0 [ M 1 2], a n d Da y 4 5 0 [ M 1 5], res pecti vel y), b ut f or o perati o nal reas o ns, 
a d mi nistrati o n of t he b o oster d ose will be dela ye d u ntil Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects 
fr o m pare nt trial D E N-3 1 5 ( Me xic o). I n s u bj ects w h o recei ve t he T D V b o oster or place b o, Visit 
4 a n d Visit 5 will o cc ur at 1 m o nt h a n d 6 m o nt hs p ost b o oster, res pecti vel y: Da y 7 5 0 ( M 2 5) a n d 
Da y 9 0 0 ( M 3 0) f or s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o)/ Da y 4 8 0 ( M 1 6) a n d Da y 6 3 0 
( M 2 1) f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States). F or all s u bj ects, Visit 1, Visi t 2, 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 4  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
a n d Visit 3 A/ 3  c orres p o n d t o 2 1 m o nt hs, 3 3 m o nt hs, a n d 3 6 m o nt hs after t he first vacci nati o n i n 
t he pri mar y vacci nati o n series, res pecti vel y. F or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o), 
Visit 3 B, Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 4 5 m o nt hs, 4 6 m o nt hs a n d 5 1 m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series, r es pecti vel y. F or s u bj ects fr o m pare nt 
trial D E N 3 0 4 ( U nite d States), Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 3 7 m o nt hs a n d 4 2 
m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series, res pecti vel y . 
2. 0  
Sec o n d ar y e n d p oi nts : 
I m m u n o ge nicit y e n d p oi nts 
A nti b o d y P ersiste nce  
•  
Ge o metric Mea n Rati o ( G M R) of ne utralizi n g a nti b o dies f or eac h of t he 4 de n g ue ser ot y pes 
f or all s u bj ects, f or all s u bj ects b y pare nt trial, a n d f or all s u bj ects b y ser ostat us at baseli ne 
i n t he pare nt trials f or: 
•  Visit 1 ( Da y 1 [ M 0]) vs Visit 2  ( Da y 3 6 0 [ M 1 2]), f or all s u bj ects. 
•  Da y 1 2 0 ( M o nt h 4) i n t he pare nt trials ( 4 m o nt hs after t he first vacci nati o n i n t he 
pri mar y vacci na ti o n series i n t he pare nt trials) vs Visit 3B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects 
fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt 
trial D E N 3 0 4 ( U nite d States)  i n t he c urre nt trial. 
•  Da y 2 7 0 ( M o nt h 9) i n t he pare nt trials ( 9 m o n t hs after t he first vacci nati o n i n t he 
pri mar y vacci nati o n series i n t he pare nt trials) vs Visit 1 ( Da y 1 [ M 0]) a n d Visit 2 ( Da y 
3 6 0 [ M 1 2]) i n t he c urre nt trial, f or all s u bj ects. 
I m pact of a T D V B o oster D ose 
•  
G M R of ne utralizi n g a nti b o dies f or eac h of t he 4 de n g ue ser ot y pes f or s u bj ects ra n d o mize d 
t o Gr o u ps 1 a n d 2 b y trial gr o u p, b y trial gr o u p a n d pare nt trial, a n d b y trial gr o u p a n d 
ser ostat us at baseli ne i n t he pare nt trials f or:  
•  
Da y 1 2 0 ( M o nt h 4) i n t he pare nt trials ( 4 m o nt hs after t he first vacci nati o n i n t he 
pri mar y vacci nati o n series i n t he pare nt trials) vs Visit 4 i n t he c urre nt trial  ( Da y 7 5 0 
[ M 2 5] f or s u bj ects fr o m pare nt trial D E N 3 1 5 [ Me xic o]/ Da y 4 8 0 [ M 1 6] f or s u bj ects 
fr o m pare nt trial D E N 3 0 4 [ U nite d States]) . 
•  
Visit 3 B ( Da y 7 2 0 [ M 2 4 ]) vs Visit 4  ( Da y 7 5 0 [ M 2 5]) f or s u bj ects fr o m pare nt trial 
D E N -3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) vs Visit 4 ( Da y 4 8 0 [ M 1 6]) f or s u bj ects 
fr o m pare nt trial D E N-3 0 4 ( U nite d States) . 
•  
Visit 3 B ( Da y 7 2 0 [ M 2 4])  vs Visit 5  ( Da y 9 0 0 [ M 3 0]) f or s u bj ects fr o m pare nt trial 
D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) vs Visit 5 ( Da y 6 3 0 [ M 2 1]) f or s u bj ects 
fr o m pare nt trial D E N 3 0 4 ( U nite d States) . 
•  
Visit 4 ( Da y 7 5 0 [ M 2 5]) vs Visit 5  ( Da y 9 0 0 [ M 3 0]) f or s u bjects fr o m pare nt trial D E N-
3 1 5 ( Me xic o)/ Visit 4 ( Da y 4 8 0 [ M 1 6 ]) vs Visit 5 ( Da y 6 3 0 [ M 2 1]) f or s u bj ects fr o m 
pare nt trial D E N -3 0 4 ( U nite d States) . 
•  
Da y 1 2 0 ( M o nt h 4) i n t he pare nt trials ( 4 m o nt hs after t he first vacci nati o n i n t he 
pri mar y vacci nati o n series i n t he pare nt trials) vs Visit 5 i n t he c urre nt trial  ( Da y 9 0 0 
[ M 3 0] f or s u bj ects fr o m pare nt trial D E N 3 1 5 [ Me xic o]/ Da y 6 3 0 [ M 2 1] f or s u bj ects 
fr o m pare nt trial D E N 3 0 4 [ U nite d States] . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 5  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
2. 0  
Sec o n d ar y e n d p oi nts :... 
Safet y e n d p oi nts  
•  
Fre q ue nc y a n d se verit y of s oli cite 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) , a n d s oli cite d s yste mic A Es f or 1 4 da ys ( da y of vacci nati o n + 1 3 da ys) 
f oll o wi n g a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3B ( Da y 7 5 0 [ M 2 5]) f or 
s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m 
pare nt trial D E N 3 0 4 ( U nite d States),  b y trial gr o u p . 
•  
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) 
f oll o wi n g a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3B ( Da y 7 5 0 [ M 2 5]) f or 
s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m 
pare nt trial D E N -3 0 4 ( U nite d States),  b y trial gr o u p.  
•  
P erce nta ge of s u bj ects wit h a n y M A A Es f oll o wi n g a d mi nistr ati o n of t he T D V b o oster or 
place b o fr o m Visit 3 B ( Da y 7 5 0 [ M 2 5]) t hr o u g h Visit 5 ( Da y 9 0 0 [ M 3 0]) f or s u bj ects fr o m 
pare nt trial D E N 3 1 5 ( Me xic o)/fr o m Visit 3 ( Da y 4 5 0 [ M 1 5]) t hr o u g h Visit 5 ( Da y 6 3 0 
[ M 2 1]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d Stat es),  b y trial gr o u p.  
•  
P erce nta ge of s u bj ects wit h a n y S A Es fr o m Visit 1 ( Da y 1 [M 0]) t hr o u g h Visit 3B ( Da y 7 5 0 
[ M 2 5]) f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or 
s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States),  pri or t o a d mi nistrati o n of t he T D V 
b o oster or place b o.   
•  
P erce nta ge of s u bj ects wit h a n y S A Es f oll o wi n g a d mi nistr ati o n of t he T D V b o oster or 
pl ace b o fr o m Visit  3 t hr o u g h Visit 5 by tri al gr o u p  fr o m Visit 3 B ( Da y 7 5 0 [ M 2 5]) after 
a d mi nistrati o n of t he T D V b o oster or place b o t hr o u g h Visit 5 ( Da y 9 0 0 [ M 3 0]) f or s u bj ects 
fr o m pare nt trial D E N-3 1 5 ( M e xic o)/fr o m Visit 3 ( Da y 4 5 0 [ M 1 5]) , after a d mi nistrati o n of 
t he T D V b o oster or place b o t hr o u g h Visit 5 ( Da y 6 3 0 [ M 2 1]) f or s u bj ects fr o m pare nt trial 
D E N -3 0 4 ( U nite d States), b y trial gr o u p . 
2. 0  
E x pl or at or y e n d p oi nts:  
A p plic a ble t o s u bjects fr o m p are nt tri al D E N -3 1 5 ( Me xic o o nly):  
•  
T he assess me nt of t he l o n g -ter m h u m oral res p o nse t o T D V will i ncl u de, b ut is n ot restrict e d 
t o, t he meas ure me nt of t he a nti -de n g ue N S 1 a nti b o d y res p o nse b y e nz y me -li n ke d 
i m m u n os or be nt assa y (a vera ge c o nce ntrati o n [relati ve u nits/ m L] of a nti-de n g ue N S 1 
a nti b o dies f or eac h of t he 4 de n g ue ser ot y pes) usi n g bl o o d sa m ples c ollecte d fr o m all 
s u bj ects at Visit 3 A/ 3 ( Da y 4 5 0 [ M 1 5]) a n d fr o m s u bj ects i n t he C MI s u bset (a p plica ble t o 
s u bj ects fr o m pare nt trial D E N -3 0 4 [ U nite d States] o nl y) at Visit 4 ( Da y 4 8 0 [ M 1 6]) a n d 
Visit 5 ( Da y 6 3 0 [ M 2 1]) . A d diti o nal e x pl orat or y tec h ni q ues ma y be a d de d as t he fiel d 
e v ol ves.  
A p plica ble t o s u bj ects fr o m  pare nt trial  D E N -3 0 4 ( U nite d St ates o nl y):  
•  
T he assess m e nt of t he l o n g -ter m h u m or al res p o nse t o T D V will i ncl u de, b ut is n ot 
restricte d t o, t he m e as ure m e nt of t he a nti-de n g ue N S 1 a nti b o dy res p o nse by 
e nzy m e -li n ke d i m m u n os or be nt assay ( aver a ge c o nce ntr ati o n [rel ative u nits/ m L] of 
a nti -de n g ue N S 1 a nti b o dies f or e ac h of t he 4 de n g ue ser oty p es) usi n g bl o o d s a m ples 
c ollecte d fr o m all s u bjects at Visit 3, a n d fr o m s u bjects i n t he C MI s u bset at Visit 4 a n d 
Visit 5. A d diti o n al e x pl or at ory t ec h ni q ues m ay be a d de d as t he fiel d ev olves.  
•  
T he assess me nt of t he l o n g -ter m cell-me diate d res p o nse t o T D V will i ncl u de, b ut is n ot 
restricte d t o, t he fre q ue nc y ( perce nta ge of s u bj ects) a n d ma g nit u de ( n u m ber of S p ot 
F or mi n g Cells [ S F C]/ 1 0 6 P B M C) of I F N -γ ELI S p ot res p o nses t o T D V usi n g bl o o d sa m pl es 
c ollecte d fr o m s u bj ects i n t he C MI s u bset at Visit 1  ( Da y 1 [ M 0]), Visit 2 ( Da y 3 6 0 [ M 1 2]), 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 6  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
Visit 3  ( Da y 4 5 0 [ M 1 5]), Visit 4 ( Da y 4 8 0 [ M 1 6]), a n d Visit 5 ( Da y 6 3 0 [ M 2 1]). Cell ular 
i m m u ne res p o nse is defi ne d as a n I F N-γ E LI S p ot res p o nse t hat is > 3 ti mes hi g her c o m pare d 
wit h bac k gr o u n d ( n o pe pti de) a n d ≥ 5 0 s p ots per  1 0 6 P B M C. A d diti o nal e x pl orat or y 
tec h ni q ues ma y be a d de d as t he fiel d e v ol ves ( C MI s u bset o nl y). 
N ote t hat t he ti mi n g of Visit 1, Visit 2, a n d Visit 3 A/ 3  will b e t he sa me f or all s u bj ects 
( Da y 1  [ M 0], Da y 3 6 0 [ M 1 2], a n d Da y 4 5 0 [ M 1 5], res pecti vel y), b ut f or o perati o nal reas o ns, 
a d mi nistrati o n of t he b o oster d ose will be dela ye d u ntil Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects 
fr o m pare nt trial D E N 3 1 5 ( Me xi c o). I n s u bj ects w h o recei ve t he T D V b o oster or place b o, Visit 
4 a n d Visit 5 will occ ur at 1 m o nt h a n d 6 m o nt hs p ost b o oster, res pecti vel y: Da y 7 5 0 ( M 2 5) a n d 
Da y 9 0 0 ( M 3 0) f or s u bj ects fr o m pare nt trial D E N
3 1 5 ( Me xic o)/ Da y 4 8 0 ( M 1 6) a n d Da y 6 3 0 
( M 2 1) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States). F or all s u bj ects, Visit 1, Visit 2, 
a n d Visit 3 A/ 3  c orres p o n d t o 2 1 m o nt hs, 3 3 m o nt hs, a n d 3 6 m o nt hs after t he first vacci nati o n i n 
t he pri mar y vacci nati o n series, res pecti vel y. F or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o), 
Visit 3 B, Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 4 5 m o nt hs, 4 6 m o nt hs a n d 5 1 m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series, r es pecti vel y. F or s u bj ects fr o m pare nt 
trial D E N 3 0 4 ( U nite d States), Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 3 7 m o nt hs a n d 4 2 
m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series, res pecti vel y.  
2. 0  
St atistic al C o nsi der ati o ns:  
T he f oll o wi n g a nal ysis sets are defi ne d f or t his trial:  
All Scree ne d: All s u bjects w h o a gree d t o p artici p ate i n t he c urre nt tri al.  
All Scree ne d -B o oster: All s u bjects w h o a gree d t o p artici p ate i n t he c urre nt tri al a n d w h o were 
scree ne d f or ‘b o oster eli gi bility’ t o deter mi ne if t hey were  eli gi ble t o g o o n t o be r a n d o mize d t o 
Gr o u p 1 or Gr o u p 2.  
R a n d o mize d Set -B o oster: All s u bjects r a n d o mize d at Visit 3 re g ar dless of w het her t hey 
receive d t he tri al v acci n ati o n i n t he c urre nt tri al. S u bjects i n t his set will be s u m m arize d 
acc or di n g t o r a n d o mize d tre at m e nt.  
2. 0  
St atistic al C o nsi der ati o ns:...  
F ull A n al ysis Set ( F A S):  All s u bj ects w h o recei ve d at least o ne d ose of T a ke d a’s T D V i n t he 
pare nt trials a n d f or w h o m t here is at least o ne vali d f oll o w -u p meas ure me nt u p t o Visit 3 B ( Da y 
7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ u p t o Visit 3 ( Da y 4 5 0 [ M 1 5]) f or 
s u bj ects fr o m pare nt trial D E N 3 0 4 ( U n ite d States) f or i m m u n o ge nicit y assess me nts i n t he 
c urre nt trial.  
F ull A n al ysis Set -B o oster ( F A S -B):  All s u bj ects w h o recei ve d at least o ne d ose of T a ke da’s 
T D V i n t he pare nt trials, t he T D V b o oster or place b o i n t he c urre nt trial, a n d f or w h o m t her e is at  
least o ne vali d f oll o w-u p meas ure me nt after a d mi nistrati o n of t he T D V b o oster or place b o at 
Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 
[ M 1 5]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d Stat es)  f or i m m u n o ge nicit y assess me nts 
i n t he c urre nt trial. 
Per Pr ot oc ol Set ( P P S):  All s u bj ects fr o m t he F A S w h o recei ve d t w o d oses of T a ke da’s T D V i n 
t he pare nt trials wit h n o ne w maj or pr ot oc ol vi olati o ns pri or t o a d mi nistrati o n of t he b o oster or 
place b o at Visit 3 B ( Da y  7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 
( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States)  t hat c o ul d p ote nti all y 
c o nf o u n d t he pri mar y e n d p oi nts i n t he c urre nt trial.  
Per Pr ot oc ol Set -B o oster ( P P S -B):  All s u b j ects fr o m t he F A S-B w h o recei ve d t w o d oses of 
T a ke d a’s T D V i n t he pare nt trials wit h n o ne w maj or pr ot oc ol vi olati o ns after a d mi nistrati o n of 
t he T D V b o oster or place b o at Visit 3B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N 3 1 5 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 7  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States)  t hat 
c o ul d p ote ntiall y c o nf o u n d t he pri mar y e n d p oi nts i n t he c urr e nt trial.  
T he maj or pr ot oc ol vi olati o n criteri o n will be defi ne d as part of a data re vie w pri or t o a nal ysis. 
T he cate g ori es of ne w 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 crit eria, 
( 2) recei vi n g t he wr o n g trial vacci nati o n at Visit 3B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m par e nt 
trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5] f or s u bjects fr o m pare nt tria l D E N 3 0 4 ( U nite d 
States);  (s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 o nl y), ( 3) recei vi n g pr o hi bite d vacci nati o ns or 
t hera pies (s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 o nl y), ( 4) perf or mi n g Visit 4 i na d missi bl y 
o utsi de t he visit wi n d o w (s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 o nl y), a n d ( 5) ot her maj or 
pr ot oc ol vi olati o ns t hat ma y b e i de ntifie d d uri n g data re vie ws.  
N ote, f or all s u bjects Visit 1 ( D ay 1 [ M 0]) a n d Visit 2 ( D ay 3 6 0 [ M 1 2]) c orres p o n d t o 
2 1  m o nt hs a n d 3 3 m o nt hs after t he first v acci n ati o n i n t he pri m ary v a cci n ati o n series i n t he 
p are nt tri al. F or s u bjects fr o m p are nt tri al D E N -3 1 5 ( Me xic o), Visit 3 ( D ay 1 2 6 0 [ M 4 2]), Visit 
4 ( D ay 1 2 9 0 [ M 4 3]), a n d Visit 5 ( D ay 1 4 4 0 [ M 4 8 ]) i n t his tri al c orres p o n d t o 6 3 m o nt hs, 6 4 
m o nt hs, a n d 6 9  m o nt hs after t he firs t v acci n ati o n i n t he pri m ary v acci n ati o n series, 
res pectively. F or s u bjects fr o m p are nt tri al D E N-3 0 4 ( U nite d St ates), Visit 3 ( D ay 4 5 0 [ M 1 5]), 
Visit 4 ( D ay 4 8 0 [ M 1 6]), a n d Visit 5 ( D ay 6 3 0 [ M 2 1]) i n t his tri al c orres p o n d t o 3 6 m o nt hs, 
3 7  m o nt hs, a n d 4 2 m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series i n t he 
p are nt tri al, res pectively.  
2. 0  
St atistic al C o nsi der ati o ns:...  
I m m u n o ge nicit y e val uati o n 
F or t he pri mar y a n d sec o n dar y i m m u n o ge nicit y e n d p oi nts (ie, G M Ts of ne utralizi n g a nti b o dies 
a n d ser o p ositi vit y rates f or eac h of t he 4 de n g ue ser ot y pes a n d m ulti ple [ 2, 3 or 4]), descri pti ve 
statistics a n d 9 5 % CIs will be pr o vi de d f or eac h a p plica ble visit  ( Visit 1, Visit 2, Visit 3, Visit 4, 
a n d Visit 5 i n t he c urre nt tri al ( Visit 1  [ Da y 1  ( M 0)], Visit 2 [ Da y 3 6 0 ( M 1 2)], Visit 3 A [ Da y 
4 5 0 ( M 1 5)], Visit 3 B [ Da y 7 2 0 ( M 2 4)], Visit 4 [ Da y 7 5 0 ( M 2 5)], a n d Visit 5 [ Da y 9 0 0 ( M 3 0)] 
i n t he c urre nt trial f or s u bj ects fr o m pare nt trial D E N-3 1 5 [ Me xic o]/ Visit 1 [ Da y 1 ( M 0)], Visit 2 
[ Da y 3 6 0 ( M 1 2)], Visit 3 [ Da y 4 5 0 ( M 1 5)], Visit 4  [ Da y 4 8 0  ( M 1 6)], a n d Visit 5 [ Da y 6 3 0 
( M 2 1)] i n t he c urre nt trial f or s u bj ects fr o m pare nt trial D E N-3 0 4 [ U nite d States] , a n d f or Da y 
1 2 0 [ M o nt h 4] a n d Da y 2 7 0 [ M o nt h 9] i n b ot h t he pare nt tri als [ w hic h c orres p o n ds t o 4  m o nt hs 
a n d 9 m o nt hs after t he first va cci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trials, 
res pecti vel y]). 
2. 0  
I m m u n o ge nicit y e val uati o n... 
F urt her details o n t he statistical a nal ysis i ncl u di n g e x pl orat or y e n d p oi nts will be pr o vi de d i n t he  
st atistic al a n alysis pl a n (S A P ). 
2. 0  
St atistic al C o nsi der ati o ns:...  
U ns olicite d A Es  
U ns olicite d A Es will be s u m marize d b y trial gr o u p f or 2 8 da ys f oll o wi n g a d mi nistrati o n of t he 
T D V  b o oster or place b o ( 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 
latest versi o n of 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. A Es lea di n g t o trial 
or vacci ne wit h dra wal wil l be s u m marize d u p t o Visit 3B ( Da y 7 2 0 [ M 2 4] 
 (pre -vacci nati o n) 
a n d t hereafter ( p ost -vacci nati o n) b y trial gr o u p u p t o Visit 5 ( Da y 9 0 0 [ M 3 0]) f or s u bj ects fr o m 
pare nt trial D E N -3 1 5 ( Me xic o)/ u p t o Visit 3 ( Da y  4 5 0  [ M 1 5]  pre -vacci nati o n) a n d t hereafter 
( p ost-vacci nati o n) b y trial gr o u p u p t o Visit 5 ( Da y 6 3 0 [ M 2 1]) f or s u bj ects fr o m pare nt tri al 
D E N -3 0 4 ( U nite d States) . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 8  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
U ns olicite d A Es will be ta b ulate d at eac h of t he f oll o wi n g le vels: o verall s u m mar y (s u bj ects wit h 
at least 1 A E), a n d b y S O C a n d P T. I n a d diti o n, 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 fr e q ue nc y greater 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 Statisti cal A nal ysis Pla n ); 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 vacci ne ( T D V b o oster or place b o). S u bj ects 
re p orti n g m ore t ha n 1 occ urre nce f or t he ter m (le vel) bei n g s u m marize d will be c o u nte d o nl y 
o nce.  
M A A Es  
M A A Es will be c ollecte d f or s u bj ects ra n d o mize d t o Gr o u p 1 a n d Gr o u p 2 a n d  will be prese nte d 
b y trial gr o u p fr o m Visit 3 B ( Da y 7 2 0 [ M 2 4])  t hr o u g h Visit 5 (Da y 9 0 0 [ M 3 0]) f or s u bj ects fr o m 
pare nt trial D E N 3 1 5 ( Me xic o)/fr o m Visit 3 ( Da y 4 5 0 [ M 1 5]) t hr o u g h Visit 5 ( Da y 6 3 0 [ M 2 1]) 
f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d Stat es). M A 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 S O C a n d P T f or eac h trial gr o u p.  
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 u p t o Visit 3B ( Da y 7 2 0 [ M 2 4])  (pre -v acci n ati o n ) a n d t he reafter 
( p ost-vacci nati o n) b y trial gr o u p u p t o Visit 5  ( Da y 9 0 0 [ M 3 0]) f or s u bj ects fr o m pare nt tri al 
D E N 3 1 5 ( Me xic o)/ u p t o Visit 3 ( Da y 4 5 0 [ M 1 5]  pre vacci nati o n) a n d t hereafter ( p ost
vacci nati o n) b y trial gr o u p u p t o Visit 5 ( Da y 6 3 0 [ M 2 1]) f or s u bj e cts fr o m pare nt trial D E N 3 0 4 
( U nite d States). 
N ote t hat t he ti mi n g of Visit 1, Visit 2, a n d Visit 3 A/ 3  will b e t he sa me f or all s u bj ects 
( Da y 1  [ M 0], Da y 3 6 0 [ M 1 2], a n d Da y 4 5 0 [ M 1 5], res pecti vel y), b ut f or o perati o nal reas o ns, 
a d mi nistrati o n of t he b o ost er d ose will be dela ye d u ntil Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects 
fr o m pare nt trial D E N 3 1 5 ( Me xic o). I n s u bj ects w h o recei ve t he T D V b o oster or place b o, Visit 
4 a n d Visit 5 will occ ur at 1 m o nt h a n d 6 m o nt hs p ost b o oster, res pecti vel y: Da y 7 5 0 ( M 2 5) a n d  
Da y 9 0 0 ( M 3 0) f or s u bj ects fr o m pare nt trial D E N
3 1 5 ( Me xic o)/ Da y 4 8 0 ( M 1 6) a n d Da y 6 3 0 
( M 2 1) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States). F or all s u bj ects, Visit 1, Visit 2, 
a n d Visit 3 A/ 3  c orres p o n d t o 2 1 m o nt hs, 3 3 m o nt hs, a n d 3 6 m o nt hs afte r t he first vacci nati o n i n 
t he pri mar y vacci nati o n series, res pecti vel y. F or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o), 
Visit 3 B, Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 4 5 m o nt hs, 4 6 m o nt hs a n d 5 1 m o nt hs 
after t he first vacci nati o n i n t he pri ma r y vacci nati o n series, r es pecti vel y. F or s u bj ects fr o m pare nt 
trial D E N 3 0 4 ( U nite d States), Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 3 7 m o nt hs a n d 4 2 
m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series, res pecti vel y . 
2. 0  
I nteri m A n al ysis: 
N o i nteri m a nal yses are pla n ne d. D ue t o si g nific a nt del ays ( of > 2 ye ars) t o b o oster 
a d mi nistr ati o n f or s u bjects fr o m p are nt tri al D E N -3 1 5 ( Me xic o), a n i nteri m a n alysis  (I A) of 
t he s afety a n d i m m u n o ge nicity d at a c ollecte d at tri al sites i n t he U nite d St ates is pl a n ne d w he n 
all s u bjects fr o m p are nt tri al D E N -3 0 4 ( U nite d St ates) h ave c o m plete d t heir l ast tri al visit 
( Visit 5 [ D ay 6 3 0 ( M 2 1)]). T his I A will be perf or m e d i n a n u n bli n de d m a n ner a n d will i ncl u de 
t he necess ary ste ps t o e ns ure t h at n o d at a b ase m o dific ati o ns are m a de after u n bli n di n g  f or 
s u bjects at tri al sites i n t he U nite d St ates. U n bli n di n g of s u bjects fr o m p are nt tri al D E N -3 1 5 
( Me xic o) will occ ur after all s u bjects at tri al sites i n Me xic o h ave c o m plete d t heir l ast tri al visit 
( Visit 5 [ D ay 1 4 4 0 ( M 4 8)]) a n d t he tri al d at a b ase h as bee n  l oc ke d. N o m o dific ati o ns t o t he 
tri al are pl a n ne d  b ase d o n t he res ults of t his  I A. A n i nteri m C S R of d at a fr o m p are nt tri al 
D E N -3 0 4 ( U nite d St ates) will n ot be pre p are d ; all tri al res ults will be re p orte d i n t he fi n al 
C S R. M ore det ails re g ar di n g t he I A  will be  pr ovi de d i n t he S A P.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 9  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
2. 1  
T a ble he a ders h ave bee n u p d ate d t o reflect mer gi n g of Visit 3 A a n d Visit 3 B at sites i n Mexic o; 
del ays t o Visit 3, Visit 4, a n d  Visit 5  at sites  i n Mexic o; a n d a n exte nsi o n of t he Visit 3 visit 
wi n d o w i n Mexic o.  
 
2. 1  
T a ble c ol u m ns u p d ate d t o reflect mer gi n g of Visit 3 A a n d Visit 3 B i n Me xic o.  
 
2. 1  
M ark re m o ve d f or “ Si g ne d I nf or me d C o nse nt/ Pe di atric Asse nt F or m ” at Week 2 as re -c o nse nt 
will t ake pl ace at Visit 3 f or s u bjects fr o m p are nt tri al D E N -3 1 5 ( Mexic o).  
 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 2 0  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
2. 1  
N ote t hat t he ti mi n g of Visit 1, Visit 2, a n d Visit 3 A/ 3  will be t he sa me f or all s u bjects ( Da y 1  [ M 0], Da y 
3 6 0 [ M 1 2], a n d Da y 4 5 0 [ M 1 5], res pecti vel y), b ut f or o perati o nal reas o ns, a d mi nistrati o n of t h e 
b o oster d ose will be dela ye d u ntil Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bjects fr o m pare nt trial D E N 3 1 5 
( Me xic o). I n s u bjects w h o recei ve t h e T D V b ooster or place b o, Visit 4 a n d Visit 5 will occ ur at 1 
m o nt h a n d 6 m o nt hs p ost b o oster, res pecti vel y: Da y 7 5 0 ( M 2 5) a n d Da y 9 0 0 ( M 3 0) f or s u bjects fr o m 
pare nt trial D E N 3 1 5 ( Me xic o)/ Da y 4 8 0 ( M 1 6) a n d Da y 6 3 0 ( M 2 1) f or s u bjects fr o m pare nt trial 
D E N -3 0 4 ( U ni te d States). F or all s u bjects, Visit 1, Visit 2, a n d Visit 3 A/ 3 c orres p o n d t o 2 1 m o nt hs, 
3 3  m o nt hs, a n d 3 6 m o nt hs after t he first vacci n ati o n i n t h e pri mar y vacci n ati o n series, res pecti vel y. 
F or s u bjects  fr o m pare nt trial D E N 3 1 5 ( Me xic o), Visit 3 B, Visit 4, a n d Visit 5 i n t his trial c orres p o n d 
t o 4 5 m o nt hs, 4 6 m o nt hs a n d 5 1 m o nt hs after t he first vacci n ati o n i n t he pri mar y va cci n ati o n series, 
res pecti vel y. F or s u bjects fr o m pare nt trial D E N 3 0 4 ( U nite d States), Visit 4, a n d Visit 5 i n t his trial 
c orres p o n d  t o 3 7 m o nt hs a n d 4 2 m o nt hs after t he first vacci n ati o n i n t he pri mar y va cci n ati o n series, 
res pecti vel y. 
N ote, f or all s u bjects Visit 1 ( D ay 1 [ M 0]) a n d Visit 2 ( D ay 3 6 0 [ M 1 2]) c orres p o n d t o 
2 1  m o nt hs a n d 3 3 m o nt hs after t he first v acci n ati o n i n t he pri m ary v a cci n ati o n series i n 
t he p are nt tri al. F or s u bjects fr o m p are nt tri al D E N-3 1 5 ( Me xic o), Visit 3 ( D ay 1 2 6 0 
[ M 4 2]), Visit 4 ( D ay 1 2 9 0 [ M 4 3]), a n d Visit 5 ( D ay 1 4 4 0 [ M 4 8 ]) i n t his tri al c orres p o n d t o 
6 3 m o nt hs, 6 4 m o nt hs, a n d 6 9  m o nt hs after t he firs t v acci n ati o n i n t he pri m ary 
v a cci n ati o n series, res pectivel y. F or s u bjects fr o m p are nt tri al D E N -3 0 4 ( U nite d St ates), 
Visit 3 ( D ay 4 5 0 [ M 1 5]), Visit 4 ( D ay 4 8 0 [ M 1 6]), a n d Visit 5 ( D ay 6 3 0 [ M 2 1]) i n t his tri al 
c orres p o n d t o 3 6 m o nt hs, 3 7  m o nt hs, a n d 4 2 m o nt hs after t he first v acci n ati o n i n t he 
pri m ary v a cci n ati o n series i n t he p are nt tri al, res pectively.  
A E = A d verse E v e nt; B MI = B o d y Mass I n de x; C MI = Cell
Me diate d I m m u nit y; M = M o nt h; 
M A A E = Me dicall y Atte n de d A d verse E ve nt; N A = N ot A p plica ble; S A E = Seri o us A d vers e E ve nt; 
S C = S u bc uta ne o us  
A E: a dverse eve nt; C MI: cell-m e di ate d im m u nity ; I C F: i nf or m e d c o nse nt f or m M: M o nt h, 
M A A E ; m e dic ally a tte n de d a dverse eve nt; N A: n ot a p plic a ble ; S A E: seri o us a dverse eve nt; 
S C:  su bc ut a ne o us.  
2. 1  
(a) At Visit 3 A, s u bj ects fr o m pare nt trial D E N
3 1 5 ( Me xic o) will be re mi n de d of a n y iss ues 
relati n g t o a d mi nistrati o n of/ or eli gi bilit y f or t he u pc o mi n g b o oster d ose at Visit 3 B. At Visit 
2, s u b j ects fr o m pare nt trial D E N 3 0 4 ( U nite d States) will b e re mi n de d of a n y iss ues 
relati n g t o a d mi nistrati o n of/ or eli gi bilit y f or t he u pc o mi n g b o oster d ose at Visit 3. T his 
i ncl u des, b ut is n ot li mite d t o, t he c ollecti o n of a n y S A Es a n d a n y A Es lea di n g t o s ubj ect 
disc o nti n uati o n or wit h dra wal, a re vie w of pr o hi bite d t hera pies, pre g na nc y a v oi da nce 
g ui da nce a n d i nf or mati o n o n a cce pta ble met h o ds of c o ntrace pti o n (f or fe male s u bj ects of 
c hil d beari n g a ge).  
( b) Visit 3  will be del aye d  u ntil  D ay 1 2 6 0 (M 4 2 ) f or s u bjects fr o m p are nt tri al D E N-3 1 5 
( Me xic o). B o oster a d mi nistrati o n a n d all b o oster relate d pr oce d ures will occ ur at Visit 3 B 
f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o) a n d at Visit 3 f or s u bj ects fr o m pare nt tri al 
D E N -3 0 4 ( U nite d States). F or s u bj ects fr o m pa re nt trial D E N-3 1 5 ( Me xic o), Visit 3 is s plit 
i nt o Visit 3 A a n d Visit 3 B t o acc o m m o date dela ye d b o oster a d mi nistrati o n. 
(c) A p plica ble o nl y t o s u bj ects ra n d o mize d t o Gr o u p 1 or Gr o u p 2 at Visit 3 B/ Visit 3.  
( d) A rete nti o n p h o ne call will be ma de bet wee n Visits 1 a n d 2 o n Da y 1 8 0 ( M 6) t o mai ntai n 
c o ntact wit h t he s u bj ect/t he s u bj ect’s le gall y acce pta ble re prese ntati ve ( L A R) a n d t o re mi n d 
t he s u bj ect/t he s u bj ect’s L A R a b o ut t he u pc o mi n g site visit. A sec o n d rete nti o n p h o ne call 
will b e ma d e t o s u bj ects fr o m pare nt tr ial D E N-3 1 5 ( Me xic o) bet wee n Visits 2 a n d 3 o n Da y 
6 3 0 ( M 2 1)  D ay 5 4 0 ( M 1 8)  t o mai ntai n c o ntact wit h t he s u bject/t he s u bj ect’s L A R bet wee n 
site visits, a n d t o re mi n d t he s u bj ect/t he s u bj ect’s L A R of t he b o oster eli gi bilit y criteria a n d 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 2 1  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
t he u pc o mi n g site visit. Fe mal e s u bj ects of c hil d beari n g a ge will als o be re mi n de d of 
pre g na nc y a v oi da nce g ui da nc e a n d acce pta ble met h o ds of c o ntrace pti o n d uri n g t his call . 
(e) Pri or t o t he s u bj ect 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 
perf or me d; u p t o 2 8  da ys pri or t o t he da y of e nr oll me nt. A d olesce nts fr o m pare nt trial 
D E N -3 1 5 ( Me xic o) w h o bec o me 1 8 years of a ge d uri n g t he c o urse of t he trial will be as ke d 
t o ret ur n t o t he i n vesti gati o nal site f or a n a d diti o nal site visit t o pr o vi de t he a p pr o priate 
writte n i nf or me d c o nse nt. T his s h o ul d be d o ne as s o o n as p ossi ble after t heir 1 8t h birt h da y.  
D ue t o c h a n ges i n t he tri al desi g n i n Me xic o ( pr ot oc ol a m e n d m e nt 3, d ate d 2 2  A u g ust  
2 0 2 2), all s u bjects fr o m p are nt tri al D E N -3 1 5 ( Me xic o) will n o w be as ke d t o re-c o nse nt 
usi n g a n u p d ate d I C F or a n u p d ate d i nf or m e d c o nse nt a n d pe di atric asse nt f or m , as 
a p plic a ble,  at Visit 3  bef ore a ny f urt her pr ot oc ol -directe d pr oce d ures are perf or m e d . D ue 
t o c ha n ges i n t he trial desi g n ( pr ot oc ol a me n d me nt 1, date d 0 9 Marc h 2 0 2 0 a n d pr ot oc ol 
a me n d me nt 2, date d 2 2 Fe br uar y 2 0 2 1), all s u bj ects will n o w be as ke d t o re c o nse nt usi n g a 
u p date d i nf or me d c o nse nt f or m(s) or u p date d i nf or me d c o nse nt a n d pe diatric asse nt f or ms at 
Visit 2 ( Da y 3 6 0 [ M 1 2]) or at t he ne xt site visit if Visit 2  has passe d bef ore a n y f urt her 
pr ot oc ol directe d pr oce d ures are perf or me d.  A n  oral s u m mar y of a n y maj or c ha n ges t hat 
ha ve bee n ma d e t o t he st u d y will be pr o vi de d t o t he s u bj ect a n d t he s u bj ect’s L A R w here 
a p plica ble i n a d diti o n t o t he I C F/ Asse nt F or m; t his  will be d oc u me nte d i n t he me dical c hart 
as part of t he re -c o nse nt pr ocess. Re -c o nse nt date s h o ul d als o be d oc u me nte d i n t he 
electr o nic Case Re p ort F or m ( e C R F).  
(f) After i nf or me d c o nse nt has be e n o btai ne d, eli gi bilit y of t he s u bj ect will be assesse d b y 
re vie w of i ncl usi o n/e xcl usi o n criteria f or trial e ntr y at Visit 1.  
( g) A re vie w of t he ‘ b o oster eli gi bilit y’ will be perf or me d pri or t o ra n d o mizati o n at Visit  3 B f or 
s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/at Visit 3 f or s u bj ects fr o m pare nt trial 
D E N 3 0 4 ( U nite d States) t o deter mi ne if t he s u bj ect is eli gi ble t o g o o n t o recei ve t he T D V 
b o oster i n t he b o oster p hase of t he trial . 
( h) Stratifie d b y pare nt trial a n d s er ostat us at baseli ne i n t he par e nt trials.  
(i) F or fe male s u bj ects of c hil d beari n g p ote ntial, pre g na nc y te sti n g ( uri ne) will be perf or me d at 
Visit  3 B f or s u bj ects fr o m par e nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 f or s u bj ects fr o m pare nt 
trial D E N 3 0 4 ( U nite d States) . Res ults m ust be c o nfir me d a n d d oc u me nte d as ne gati ve pri or 
t o a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3 B/ Visit 3, as a p plica ble . 
A d diti o nal pre g na nc y tests ma y be perf or me d d uri n g t he trial if dee me d necessar y b y t he 
i n vesti gat or; w here t he res ults of a uri ne pre g na nc y test are i n d o u bt, a ser u m pre g na nc y test 
will b e perf or me d t o verif y t h e res ult.  
(j) A n y rele va nt i nf or mati o n c oll ecte d d uri n g t he pare nt trials will be accesse d via t he data b ase 
a n d u p date d as necessar y t hr o u g h o ut t he trial c o n d uct.  
( k) All 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 t he T D V 
b o oster or place b o at Visit  3 B/ Visit 3, as a p plica ble,  a n d 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 Visit  3 B/ Visit 3, as 
a p plica ble ,; 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 Visit 3 B/ Visit 3 , 
as a p plica ble ,; 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 Visit 3 B/ Visit 3 , as 
a p plica ble . 
(l) A n y i nacti vate d vacci nes a d mi nistere d ≤1 4 da ys pri or t o bl o o d sa m ple c ollecti o n a n d T D V 
b o oster/ place b o a d mi nistrati o n at Visit 3 B/ Visit 3, as a p plic a ble, a n d a n y li ve atte n uate d 
vacci nes a d mi nistere d ≤2 8 da ys pri or t o bl o o d sa m ple c olle cti o n or T D V b o oster/ place b o 
a d mi nistrati o n at Visit 3 B/ Visit 3, as a p plica ble . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 2 2  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
( m) 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 MI b o dy m ass i n de x  
will b e calc ulate d a ut o maticall y.  
( n) S u bj ects ma y u n der g o a tar get e d 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 ( Visit 1) 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. 
( o) 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 p erat ure.  
( p) S u bj ects will be pr o vi de d wit h i nf or mati o n o n acce pta 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 oc ess a n d will be as ke d t o si g n a c o nse nt f or m at Visit 1 
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 va.  F or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o), f urt her g ui da nce wit h res pect t o t he 
a v oi da nce of pre g na n c y will b e pr o vi de d t o all fe male s u bj ects of c hil d beari n g p ote ntial at 
Visit 3 A a n d t o all fe male s u bj ects of c hil d beari n g p ote ntial w h o are ra n d o mize d t o Gr o u p 1 
or 2 at Visit  3 B,  a n d at Visit 4 . F or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States),  
fF urt her g ui da nce wit h res pect t o t he a v oi da nce of pre g na nc y will be pr o vi de d t o all fe mal e 
s u bj ects of c hil d beari n g p ote ntial at Visit 2 a n d t o all fe male s u bj ects of c hil d beari n g 
p ote ntial w h o are ra n d o mize d t o Gr o u p 1 or 2 at Visit  3 , a n d at Visit 4 . Fe ma les of 
c hil d beari n g p ote ntial, w h o ar e ra n d o mize d t o Gr o u p 1 or 2 a n d are se x uall y acti ve, will als o 
be re mi n de d t o a d here t o acce pta ble c o ntrace pti ve met h o ds f or u p t o 6 wee ks after T D V 
b o oster or place b o a d mi nistrati o n.  
( q) S u bj ects w h o meet t he criteria f or  ‘ b o oster eli gi bilit y’ a n d are s u bse q ue ntl y ra n d o mize d t o 
Gr o u p 1 or Gr o u p 2  at Visit 3 B f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o) / Visit 3 f or 
s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States),  will recei ve t he T D V b o oster or 
place b o, res pecti vel y.  
(r) I nj ecti o n site pai n, er yt he ma, a n d s welli n g assesse d b y trial staff f or 3 0 mi n utes 
p ost -vacci nati o n.  
(s) Diar y car ds ( pa p er or electr o nic) will be distri b ute d t o s u bj ects i n Gr o u ps 1 a n d 2 at Visit 
3 B/ Visit 3, as a p plica ble , f or t he c ollecti o n of 1) 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 s u bse q ue nt da ys) f oll o wi n g T D V b o oster or place b o 
a d mi nistrati o n, a n d 2) s olicite d s yste mic A Es f or 1 4  da ys ( d a y of vacci nati o n + 1 3 
s u bse q ue nt d a ys) f oll o wi n g T D V b o oster or place b o a d mi n istrati o n. 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 of s olicite d 
s yste mic A Es t o vacci ne a d mi nistrati o n (relate d or n ot relate d).  
(t) U ns olicite d A Es will be c ollecte d b y i nter vie w a n d rec or de d f or Gr o u ps 1 a n d 2 f or 2 8 da ys 
( da y of vacci nati o n + 2 7 s u bse q ue nt da ys) f oll o wi n g T D V b o oster or place b o 
a d mi nistrati o n. T he i n vesti gat or will cate g orize eac h e ve nt b y se verit y ( mil d, m o derate or 
se vere) a n d will assess ca usalit y t o trial vacci ne a d mi nistrati o n (relate d or n ot relate d). If 
s olicite d l ocal (i nj ecti o n site) reacti o ns a n d s yste mic A Es c o nti n ue o n Da y 8 a n d Da y 1 5 
(after a d mi nistrati o n of t he T D V b o oster or place b o), res pecti vel y, rec or d t he f ull d urati o n 
of t he e ve nt o n t he “ A d verse E ve nt” e C R F.  
( u) M A A Es will be c ollecte d f or Gr o u ps 1 a n d 2 fr o m Visit 3 B/ Visit 3, as a p plica ble , t hr o u g h 
Visit 5.  
( v) A n y S A Es a n d a n y A Es lea di n g t o s u bj ect disc o nti n uati o n or wit h dra wal will be c ollecte d 
f or all s u bj ects f or t he trial d urati o n. 
( w) At Visit 3 A/ 3 , a 1 0 m L blo o d sa m ple a n d 4 0 m L bl o o d sa m ple will be ta ke n fr o m all 
s u bj ects. F or t h ose s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States) w h o are ra n d o mize d 
t o Gr o u ps 1 a n d 2 at Visit 3, all bl o o d sa m ples s h o ul d be ta ke n pri or t o a d mi nistrati o n of t he 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 2 3  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
T D V b o oster d o se or place b o. A n a d diti o nal 1 0 m L bl o o d sa m ple will als o be c ollecte d pri or 
t o a d mi nistrati o n of t he T D V b o oster d ose or place b o at Visit 3 B fr o m s u bj ects fr o m pare nt 
trial D E N 3 1 5 ( Me xic o) ra n d o mize d t o Gr o u ps 1 a n d 2 at Visit 3 B.  T he bl o o d sa m ples ta ke n  
at Visit 4  s h o ul d be ta ke n at le ast 2 9 da ys (-1, + 7 da ys) after a d mi nistrati o n of t he T D V 
b o oster or place b o at eit her Visit 3 B/ Visit 3.  
( x) O ne a d diti o n al 4 0 m L bl o o d s a m ple will be c ollecte d fr o m a s u bset of 5 0 s u bjects ( C MI 
s u bset; fr o m D E N-3 0 4 o nly) f or e x pl or at ory i m m u n o ge nicity a n alyses fr o m Visit 1 
t hr o u g h Visit 5. A n a d diti o n al 1 0 m L bl o o d s a m ple will als o be c ollecte d fr o m s u bjects i n 
t he C MI s u bset at Visit 4 a n d Visit 5 f or f urt her e x pl or at ory i m m u n o ge nicity a n alyses. 
3. 3  
I A           i nteri m a nal ysis 
T D V -1   de n g ue ser ot y pes 2/ 1 rec o m bi na nt c hi meric strai n 
T D V -3   de n g ue ser ot y pes 2/ 3 rec o m bi na nt c hi meric strai n 
T D V -4   de n g ue ser ot y pes 2/ 4 rec o m bi na nt c hi meric strai n 
3. 4  
Secti o n delete d  
3. 4   C or p or ate I detific ati o n  
T V                   T a ke d a Vacci nes, I nc.  
4. 1  
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 niz e d ser ot y pes, de n g ue vir us ser oty pe -1, -2, -3, a n d -4 ( D E N V -1, 
D E N V -2, D E N V -3, or a n d  D E N V -4 ). 
4. 1  
A first tetra vale ntrec o m bi n a nt de n g ue vacci ne (c hi meric yell o w fe ver vir us de n g ue 
vir us -tetra vale nt d e n g ue vacci ne [ C Y D-T D V]) was a p pr o ve d i n s o me c o u ntries i n Asia a n d 
Lati n A merica i n 2 0 1 5, i n E ur o pe i n 2 0 1 8, a n d i n t he U nite d States i n 2 0 1 9 [ 1 0]. I nitial fi n di n gs 
s h o we d t hat vacci ne efficac y was differe nt bet wee n ser ot y p es a n d de pe n de d o n de n g ue 
pre -e x p os ure stat us [ 1 1]. F urt her a nal yses s h o we d t hat pe o ple w h o ha d n ot bee 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 if t he y were i nfecte d 
after vacci nati o n wit h C Y D -T D V [ 1 2]. I n a revise d Str ate gic A dvis ory Gr o u p of E x perts o n 
I m m u niz ati o n ( S A G E) rec o m m e n d ati o n i n A pril 2 0 1 8, t he S A G E c o ncl u de d t h at f or c o u ntries 
c o nsi deri n g C Y D -T D V v a cci n ati o n as p art of t heir de n g ue c o ntr ol pr o gr a m, a “ pre 
v a cci n ati o n scree ni n g str ate g y ” w o ul d be t he preferre d o pti o n, i n w hic h o nly 
de n g ue -ser o p ositive pers o ns are v acci n ate d. He nce, t here is a c o nti n ue d u n met p u blic he alt h 
nee d f or safer a n d m ore effica ci o us de n g ue vacci nes.  
4. 1  
T a ke d a’s De n g ue Tetr a v ale nt De n g ue V acci ne C a n di d ate ( Live, Atte n u ate d) ( T D V) - 
B ac k gr o u n d : 
T a ke d a’s T D V  c o nsists of 1 m olec ularl y c haracterize d, atte n uate d de n g ue ser ot y pe 2 vir us strai n 
a n d 3 rec o m bi na nt c hi meric 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 
de n g ue ser ot y pes  1 4  1, 3, a n d 4 . 
4. 1  
T a ke d a’s 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 rec o m bi na nt  c hi meric , att e n uate d vacci ne strai ns f or de n g ue ser ot y pes 1, 3 a n d 4 wer e 
e n gi neere d b y s u bstit ut i 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 D V -2 wit h t he pr M a n d E ge nes fr o m 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, res pecti vel y [ 1 4]. T h us, T a ke d a’s T D V is c o m prise d of 4 de n g ue vir us 
strai ns: T D V -2 ( 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 c hi meric strai n ( T D V-1), a de n g ue ser ot y pes 2/ 3  rec o m bi na nt 
c hi meric 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 c hi meric strai n ( T D V-4) . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 2 4  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
4. 1  
T a ke d a’s 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:...  
N o ncli nical st u dies carrie d o ut i n mice a n d n o n h u ma n pri mat es ha ve de m o nstrate d  a n acce pta ble 
safet y, i m m u n o ge nicit y, a n d efficac y pr ofile f or T a ke da’s T D V . A d diti o nall y, dD ata 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 nicit y, 
safet y a n d i m m u n o ge nicit y pr ofiles f or T a ke da’s T D V  i n he alt h y a d ults i n n o n-e n de mic ar eas 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 
cC o m plete d p hase 2 cli nical trials ha ve e na ble d t he selecti o n of a fi nal T D V  d ose (i n a 
l y o p hilize d f or m ulati o n) a n d a t w o2 -d ose vacci nati o n series 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 cli nic al devel o p m e nt  
pr o gra m. I n J a n uar y 2 0 1 9,Res ults fr o m  t he pi v otal D E N-3 0 1 efficac y trial s h o we d t h at t h e met 
its pri ma r y e n d p oi nt w as m et, de m o nstrati n g t hat T D V was efficaci o us i n pre ve nti n g de n g ue 
fe ver i n c hil dre n a n d a d olesce nts li vi n g i n de n g ue-e n de mic c o u ntries [ 1 5]. T D V h as bee n give n 
t o >2 0 ,0 0 0 cli nic al tri al s u bje cts. All a vaila ble data als o s h o we d t hat T D V was w ell t olerate d 
wit h n o si g nifica nt safet y c o nc er ns t o date [ 1 5 1 6 ]. 
4. 2  
S u bj ects pre vi o usl y e nr olle d i n t w o pare nt trials ( D E N -3 0 4 a n d D E N -3 1 5) will i nitiall y be 
i n vite d t o partici pate i n t he D E N-3 0 3 f oll o w -u p trial fr o m 2 1 m o nt hs after t he first vacci nati o n i n 
t he pri mar y vacci nati o n series i n t he pare nt trials. T he i ncl usi o n  of s u bj ects fr o m ot her trials 
wit hi n t he T D V pr o gra m ma y als o be c o nsi dere d if t he y meet t he eli gi bilit y criteria f or e ntr y i nt o 
D E N 3 0 3. A nti b o d y persiste nce will be assesse d i n all s u bj ects f or u p t o 4 5 6 3 m o nt hs after t he 
first vacci nati o n i n t he pri mary vacci nati o n series f or s u bj ects fr o m pare nt trial D E N -3 1 5 
( Me xic o) a n d f or u p t o 3 6 m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n seri es f or 
s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States).  
5. 1. 1  
•  
T o descri be a nti b o d y persiste nce f or eac h of t he 4 de n g ue ser ot y pes f or u p t o 4 5 6 3 m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series f or s u bj ects fr o m pare nt trial 
D E N -3 1 5 ( Me xic o) a n d f or u p t o 3 6 m o nt hs after t he first va cci nati o n i n t he pri mar y 
vacci nati o n series f or s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nite d States).  
5. 1. 2  
A nti b o d y P ersis te nce 
•  
T o descri be t he o verall tre n d i n a nti b o d y deca y f or all 4 de n g ue ser ot y pes fr o m val ues 
o btai ne d after t he pri mar y vac ci nati o n series i n t he pare nt tri als t hr o u g h 4 5 6 3  m o nt hs after 
t he first vacci nati o n i n t he pri mar y vacci nati o n series f or s u bj ects fr o m pare nt trial D E N-3 1 5 
( Me xic o) a n d t hr o u g h 3 6 m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n seri es 
f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States).  
I m pact of a T D V B o oster D ose 
•  
T o descri be t he i m pact of a T D V b o oster o n a nti b o d y res p o nse f or eac h of t he 4 de n g ue 
ser ot y pes f or u p t o 5 1 6 9 m o nt hs f oll o wi n g t he first vacci nati o n i n t he pri mar y vacci nati o n 
series f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o) a n d f or u p t o 4 2  m o nt hs f oll o wi n g 
t he first vacci nati o n i n t he pri mar y vacci nati o n series f or s u bj ects fr o m pare nt trial D E N-3 0 4 
( U nite d States). 
S afety  
•  
T o descri be t he l o n g -ter m safet y of T a ke da’s T D V f or u p t o 4 5 6 3 m o nt hs i n pre vi o usl y 
vacci nate d s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o) a n d f or u p t o 3 6 m o nt hs i n 
pre vi o usl y vacci nate d s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nite d States).  
5. 1. 3  
A p plic a ble t o s u bjects fr o m p are nt tri al D E N-3 1 5 ( Me xic o o nly):  
•  
T o e val uate as pects of t he l o n g -ter m h u m oral i m m u ne res p o nse t o T a ke da’s T D V i n all 
s u bj ects at 3 6 6 3  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he 
pare nt trial  ( D E N-3 1 5) s a n d i n t he cell -me diate d i m m u nit y ( C MI) s u bset (a p plica ble t o 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 2 5  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
s u bj ects fr o m pare nt trial D E N 3 0 4 [ U nite d States] o nl y) at 1 m o nt h a n d 6 m o nt hs p ost 
b o oster i n t he c urre nt trial ; t his is i ncl usi ve of, b ut n ot restricte d t o, a n assess me nt of t he 
a nti -de n g ue N o n -Str uct u ral pr otei n 1 ( N S 1) a nti b o d y res p o nse.  
A p plica ble t o s u bj ects fr o m pare nt trial  D E N -3 0 4 ( U nite d St ates o nl y):  
•  
T o ev al u ate as pects of t he l o n g -ter m h u m or al i m m u ne res p o nse t o T a ke d a’s T D V i n all 
s u bjects at 3 6 m o nt hs after t h e first v acci n ati o n i n t he pri m ary v acci n ati o n series i n t he 
p are nt tri al  ( D E N-3 0 4) , a n d i n t he cell-m e di ate d i m m u nity (C MI ) s u bset at 1 m o nt h a n d 
6  m o nt hs p ost b o oster i n t he c urre nt tri al; t his is i ncl usive of, b ut n ot restricte d t o, a n 
assess m e nt of t he a nti -de n g ue N S 1 a nti b o dy r es p o nse.  
•  
T o e val uate as pects of t he l o n g -ter m cell-me diate d i m m u ne res p o nse t o T a ke da’s T D V u p t o 
3 6 m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trial 
( D E N-3 0 4)  a n d at 1 m o nt h a n d 6 m o nt hs p ost b o oster i n t he c urre nt trial; t his is i ncl usi ve of, 
b ut n ot restricte d t o, t he ma g nit u de (I nterfer o n -ga m ma E nz y me -Li n ke d I m m u n os p ot [I F N -γ 
E LI S p ot]) of t he l o n g -ter m T cell-me diate d i m m u ne res p o ns e t o T D V ( C MI s u bset o nl y) . 
5. 2  
N ote, f or all s u bjects Visit 1 ( D ay 1 [ M 0]) a n d Visit 2 ( D ay 3 6 0 [ M 1 2]) c orres p o n d t o 
2 1  m o nt hs a n d 3 3 m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series i n 
t he p are nt tri al. F or s u bjects fr o m p are nt tri al D E N -3 1 5 ( Me xic o), Visit 3 ( D ay 1 2 6 0 
[ M 4 2]), Visit 4 ( D ay 1 2 9 0 [ M 4 3]), a n d Visit 5 ( D ay 1 4 4 0 [M 4 8 ]) i n t his tri al c orres p o n d t o 
6 3 m o nt hs, 6 4 m o nt hs, a n d 6 9  m o nt hs after t he first v acci n ati o n i n t he pri m ary 
v a cci n ati o n series, res pectivel y. F or  s u bjects fr o m p are nt tri al D E N-3 0 4 ( U nite d St ates), 
Visit 3 ( D ay 4 5 0 [ M 1 5]), Visit 4 ( D ay 4 8 0 [ M 1 6]), a n d Visit 5 ( D ay 6 3 0 [ M 2 1]) i n t his tri al 
c orres p o n d t o 3 6 m o nt hs, 3 7  m o nt hs, a n d 4 2 m o nt hs after t he first v acci n ati o n i n t he 
pri m ary v a cci n ati o n series  i n t he p are nt tri al, res pectively. 
5. 2. 1  
•  
Ge o metric mea n titers ( G M Ts) of ne utralizi n g a nti b o dies ( b y micr o ne utralizati o n test 5 0 % 
[ M N T5 0]) f or eac h of t he 4 de n g ue ser ot y pes a n d ser o p ositi vit y rates ( % of s u bj ects wit h 
reci pr ocal ne utralizi n g titer ≥1 0) f or eac h of t he 4 de n g ue ser ot y pes a n d m ulti ple ( 2, 3 or 4) 
at Visit 1  ( Da y 1 [ M 0]), Visit  2 ( Da y 3 6 0 [ M 1 2]), a n d Visit  3 A ( Da y 4 5 0 [ M 1 5]), a n d Visit 
3 B ( Da y 7 2 0 [ M 2 4] ; (pri or t o a d mi nistrati o n of t he T D V b o oster or place b o f or s u bj ects 
ra n d o mize d t o Gr o u ps 1 a n d 2, res pecti vel y) f or s u bj ects fr o m pare nt trial D E N-3 1 5 
( Me xic o) a n d at Visit 1 ( Da y 1 [ M 0]), Visit 2 ( Da y 3 6 0 [ M 1 2]), a n d Visit 3 ( Da y 4 5 0 
[ M 1 5]; pri or t o a d mi nistrati o n of t he T D V b o oster or place b o f or s u bj ects ra n d o mize d t o 
Gr o u ps 1 a n d 2, res pecti vel y) f or s u bj ects fr o m pare nt trial D E N
3 0 4 ( U nite d States),  
s u m marize d f or all s u bj ects, f or all s u bj ects b y pare nt trial, a n d f or all s u bj ects b y ser ostat us 
at baseli ne i n t he pare nt trials.  
•  
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 a n d 
ser o p ositi vit y rates ( % of s u bj ects wit h reci pr ocal ne utralizi n g titer ≥1 0) f or eac h of t he 
4  de n g ue ser ot y pes a n d m ulti ple ( 2,  3  or 4) at V isit 4 ( Da y 7 5 0 [ M 2 5] f or s u bj ects fr o m 
pare nt trial D E N -3 1 5 [ Me xic o]/ Da y 4 8 0 [ M 1 6] f or s u bj ects fr o m pare nt trial D E N -3 0 4 
[ U nite d States]) a n d Visit 5 ( Da y 9 0 0 [ M 3 0] f or s u bj ects fr o m pare nt trial D E N-3 1 5 
[ Me xic o]/ Da y 6 3 0 [ M 2 1] f or s u bj ects fr o m pare nt tr ial D E N 3 0 4 [ U nite d States]), f or 
s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 b y trial gr o u p, b y tri al gr o u p a n d pare nt trial, a n d b y 
trial gr o u p a n d ser ostat us at baseli ne i n t he pare nt trials. 
N ote t hat t he ti mi n g of Visit 1, Visit 2, a n d Visit 3 A/ 3  will b e t he sa me f or all s u bj ects 
( Da y 1  [ M 0], Da y 3 6 0 [ M 1 2], a n d Da y 4 5 0 [ M 1 5], res pecti vel y), b ut f or o perati o nal reas o ns, 
a d mi nistrati o n of t he b o oster d ose will be dela ye d u ntil Visit 3 B ( Da y 7 2 0  [ M 2 4]) f or s u bj ects 
fr o m pare nt trial D E N 3 1 5 ( Me xic o). I n s u bj ects w h o recei ve t he T D V b o oster or place b o, Visit 
4 a n d Visit 5 will occ ur at 1 m o nt h a n d 6 m o nt hs p ost b o oster, res pecti vel y: Da y 7 5 0 ( M 2 5) a n d 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 2 6  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
Da y 9 0 0 ( M 3 0) f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Da y 4 8 0 ( M 1 6) a n d Da y 6 3 0 
( M 2 1) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States). F or all s u bj ects, Visit 1, Visit 2, 
a n d Visit 3 A/ 3  c orres p o n d t o 2 1 m o nt hs, 3 3 m o nt hs, a n d 3 6 m o nt hs after t he first vacci nati o n i n 
t he pri mar y vacci nati o n series, res pecti vel y. F or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o), 
Visit 3 B, Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 4 5 m o nt hs, 4 6 m o nt hs,  a n d 5 1 m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series, r es pecti vel y. F or s u bj e cts fr o m pare nt 
trial D E N 3 0 4 ( U nite d States), Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 3 7 m o nt hs a n d 
4 2  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series, res pecti vel y . 
5. 2. 2  
I m m u n o ge nicit y E n d p oi nts: 
A nti b o dy Persiste nce  
•  
Ge o metric Mea n Rati o ( G M R) of ne utralizi n g a nti b o dies f or eac h of t he 4 de n g ue ser ot y pes 
f or all s u bj ects, f or all s u bj ects b y pare nt trial, a n d f or all s u bj ects b y ser ostat us at baseli ne 
i n t he pare nt trials f or: 
•  
Visit 1 ( Da y 1 [ M 0]) vs Visit 2 ( Da y 3 6 0 [ M 1 2]), f or all s u bj ects. 
•  
Da y 1 2 0 ( M o nt h 4) i n t he pare nt trials ( 4 m o nt hs after t he first vacci nati o n i n t he pri mar y 
vacci nati o n series i n t he pare nt trials) vs Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt 
trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 
( U nite d States) i n t he c urre nt trial. 
•  
Da y 2 7 0 ( M o nt h 9) i n t he pare nt trials ( 9 m o nt hs after t he first vacci nati o n i n t he pri ma r y 
vacci nati o n series i n t he pare nt trials) vs Visit 1 ( Da y 1 [ M 0]) a n d Visit 2 ( Da y 3 6 0 [ M 1 2]) 
i n t he c urre nt trial, f or all s u bj ects. 
5. 2. 2  
I m p act of a T D V B o oster D ose. .. 
•  
Da y 1 2 0 ( M o nt h 4) i n t he pare nt trials ( 4 m o nt hs after t he first vacci nati o n i n t he pri mar y 
vacci nati o n series i n t he pare nt trials) vs Visit 4 i n t he c urre nt trial  (Da y 7 5 0 [ M 2 5]  f or 
s u bj ects fr o m pare nt trial D E N 3 1 5 [ Me xic o]/ Da y 4 8 0 [ M 1 6 ] f or s u bj ects fr o m pare nt trial 
D E N -3 0 4 [ U nite d States]) . 
•  
Visit 3 B ( Da y 7 2 0 [ M 2 4] ) vs Visit 4 (Da y 7 5 0 [ M 2 5] ) f or s u bj ects fr o m pare nt trial D E N-
3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) vs Visit 4 ( Da y 4 8 0 [ M 1 6]) f or s u bj ects fr o m pare nt 
trial D E N-3 0 4 ( U nite d  States) . 
•  
Visit 3 B ( Da y 7 2 0 [ M 2 4])  vs Visit 5  ( Da y 9 0 0 [ M 3 0]) f or s u bj ects fr o m pare nt trial D E N
3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) vs Visit 5 ( Da y 6 3 0 [ M 2 1]) f or s u bj ects fr o m pare nt 
trial D E N 3 0 4 ( U nite d States) . 
•  
Visit 4 ( Da y 7 5 0 [ M 2 5]) vs Visit 5  ( Da y 9 0 0 [ M 3 0] ) f or s u bjects fr o m pare nt trial D E N-3 1 5 
( Me xic o)/ Visit 4 ( Da y 4 8 0 [ M 1 6]) vs Visit 5 ( Da y 6 3 0 [ M 2 1]) f or s u bj ects fr o m pare nt trial 
D E N -3 0 4 ( U nite d States) . 
•  
Da y 1 2 0 ( M o nt h 4) i n t he pare nt trials ( 4 m o nt hs after t he first vacci nati o n i n t he pri ma r y 
vacci nati o n series i n t he pare nt trials) vs Visit 5 i n t he c urre nt trial  ( Da y 9 0 0 [ M 3 0] f or 
s u bj ects fr o m pare nt trial D E N 3 1 5 [ Me xic o]/ Da y 6 3 0 [ M 2 1] f or s u bj ects fr o m pare nt trial 
D E N 3 0 4 [ U nite d States]) . 
5. 2. 2  
S afet y E n d p oi nts:  
•  
Fre q ue nc y a n d se verit y of s oli cite 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) , a n d s oli cite d s yste mic A Es f or 1 4 da ys ( da y of vacci nati o n + 1 3 da ys) 
f oll o wi n g a d mi nistrati o n of t he T D V b o oster or place b o at Visit  3 B ( Da y 7 2 0 [ M 2 4])  f or 
s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m 
pare nt trial  D E N 3 0 4 ( U nite d States),  b y trial gr o u p.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 2 7  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
•  
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) 
f oll o wi n g a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or 
s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m 
pare nt trial D E N -3 0 4 ( U nite d States),  b y trial gr o u p.  
•  
P erce nta ge of s u bj ects wit h a n y me dicall y atte n de d a d verse e ve nts ( M A A Es) f oll o wi n g 
a d mi nistrati o n of t he T D V b o oster or place b o fr o m Visit 3 B ( Da y 7 2 0 [ M 2 4]) t hr o u g h 
Visit  5 ( Da y 9 0 0 [ M 3 0]) f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/fr o m Visit 3 ( Da y 
4 5 0 [ M 1 5]) t hr o u g h Visit 5 ( Da y 6 3 0 [ M 2 1]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 
( U nite d States), b y trial gr o u p.  
•  
P erce nta ge of s u bj ects wit h a n y seri o us a d verse e ve nts ( S A Es) fr o m Visit 1 ( Da y 1 [ M 0]) 
t hr o u g h Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 
( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States),  pri or t o 
a d mi nistrati o n of t he T D V b o oster or place b o.  
•  
P erce nta ge of s u bj ects wit h a n y S A Es f oll o wi n g a d mi nistr ati o n of t he T D V b o oster or 
pl ace b o fr o m Visit  3 t hr o u g h Visit 5 by tri al gr o u p  fr o m Visit 3 B ( Da y 7 2 0 [ M 2 4]) after 
a d mi nistrati o n of t he T D V b o oster or place b o t hr o u g h Visit 5 ( Da y 9 0 0 [ M3 0])  f or s u bj ects 
fr o m pare nt trial D E N 3 1 5 ( Me xic o)/fr o m Visit 3 ( Da y 4 5 0 [ M 1 5]) , after a d mi nistrati o n of 
t he T D V b o oster or place b o t hr o u g h Visit 5 ( Da y 6 3 0 [ M 2 1]) f or s u bj ects fr o m pare nt trial 
D E N -3 0 4 ( U nite d States), b y trial gr o u p . 
N ote t hat t he ti mi n g of Visit 1, Visit 2, a n d Visit 3 A/ 3  will b e t he sa me f or all s u bj ects 
( Da y 1  [ M 0], Da y 3 6 0 [ M 1 2], a n d Da y 4 5 0 [ M 1 5], res pecti vel y), b ut f or o perati o nal reas o ns, 
a d mi nistrati o n of t he b o oster d ose will be dela ye d u ntil Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects 
fr o m pare nt trial D E N 3 1 5 ( Me xic o). I n s u bj ects w h o recei ve t he T D V b o oster or place b o, Visit 
4 a n d Visit 5 will occ ur at 1 m o nt h a n d 6 m o nt hs p ost b o oster, res pecti vel y: Da y 7 5 0 ( M 2 5) a n d 
Da y 9 0 0 ( M 3 0) f or s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o)/ Da y 4 8 0 ( M 1 6) a n d Da y 6 3 0 
( M 2 1) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States). F or all s u bj ects, Visit 1, Visit 2, 
a n d Visit 3 A/ 3  c orres p o n d t o 2 1 m o nt hs, 3 3 m o nt hs, a n d 3 6 m o nt hs after t he first vacci nati o n i n 
t he pri mar y vacci nati o n series, res pecti vel y. F or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o), 
Visit 3 B, Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 4 5 m o nt hs, 4 6 m o nt hs,  a n d 5 1 m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series, r es pecti vel y. F or s u bj e cts fr o m pare nt 
trial D E N-3 0 4 ( U nite d States), Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 3 7 m o nt hs a n d 
4 2  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series, res pecti vel y . 
5. 2. 3  
A p plic a ble t o s u bjects fr o m p are nt tri al D E N -3 1 5 ( Me xic o o nly):  
•  
T he assess me nt of t he l o n g -ter m h u m oral res p o nse t o T D V will i ncl u de, b ut is n ot restrict e d 
t o, t he meas ure me nt of t he a nti-de n g ue N S 1 a nti b o d y res p o nse b y e nz y me -li n ke d 
i m m u n os or be nt assa y (a vera ge c o nce ntrati o n [relati ve u nits/ m L] of a nti-de n g ue N S 1 
a nti b o dies f or eac h of t he 4 de n g ue ser ot y pes) usi n g bl o o d sa m ples c ollecte d fr o m all 
s u bj ects at Visit 3A/ 3 ( Da y 4 5 0 [ M 1 5]) a n d fr o m s u bj e cts i n t he C MI s u bset (a p plica ble t o 
s u bj ects fr o m pare nt trial  D E N -3 0 4 [ U nite d States] o nl y) at Visit 4 ( Da y 4 8 0 [ M 1 6]) a n d 
Visit 5 ( Da y 6 3 0 [ M 2 1]) . A d diti o nal e x pl orat or y tec h ni q ues ma y be a d de d as t he fiel d 
e v ol ves.  
A p plica ble t o s u bj ects fr o m pare nt tr ial D E N -3 0 4 ( U nite d St ates o nl y):  
•  
T he assess m e nt of t he l o n g -ter m h u m or al res p o nse t o T D V will i ncl u de, b ut is n ot 
restricte d t o, t he m e as ure m e nt of t he a nti-de n g ue N S 1 a nti b o dy res p o nse by 
e nzy m e -li n ke d i m m u n os or be nt ass ay ( aver a ge c o nce ntr ati o n [rel ative u nits/ m L] of 
a nti -de n g ue N S 1 a nti b o dies f or e ac h of t he 4 de n g ue ser oty p es) usi n g bl o o d s a m ples 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 2 8  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
c ollecte d fr o m all s u bjects at Visit 3, a n d fr o m s u bjects i n t he C MI s u bset at Visit 4 a n d 
Visit 5. A d diti o n al e x pl or at ory tec h ni q ues m ay be a d de d as t he fiel d  ev olves.  
•  
T he assess me nt of t he l o n g -ter m cell-me diate d res p o nse t o T D V will i ncl u de, b ut is n ot 
restricte d t o, t he fre q ue nc y ( perce nta ge of s u bj ects) a n d ma g nit u de ( n u m ber of S p ot 
F or mi n g Cells [ S F C]/ 1 0 6 P B M C) of I F N -γ E LI S p ot res p o nses t o T D V usi n g bl o o d sa m pl es 
c ollecte d fr o m s u bj ects i n t he C MI s u bset at Visit 1  ( Da y 1 [ M 0]), Visit 2 ( Da y 3 6 0 [ M 1 2]), 
Visit 3  ( Da y 4 5 0 [ M 1 5]), Visit 4 ( Da y 4 8 0 [ M 1 6]), a n d Visit 5 ( Da y 6 3 0 [ M 2 1]). Cell ular 
i m m u ne res p o nse is defi ne d as a n I F N-γ E LI S p ot res p o nse t hat is > 3 ti mes hi g her c o m pare d 
wit h bac k gr o u n d ( n o pe pti de) a n d ≥ 5 0 s p ots per  1 0 6 P B M C. A d diti o nal e x pl orat or y 
tec h ni q ues ma y be a d de d as t he fiel d e v ol ves ( C MI s u bset o nl y). 
N ote t hat t he ti mi n g of Visit 1, Visi t 2, a n d Visit 3 A/ 3 will b e t he sa me f or all s u bj ects 
( Da y 1  [ M 0], Da y 3 6 0 [ M 1 2], a n d Da y 4 5 0 [ M 1 5], res pecti vel y), b ut f or o perati o nal reas o ns, 
a d mi nistrati o n of t he b o oster d ose will be dela ye d u ntil Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects 
fr o m pare nt trial D E N-3 1 5 ( Me xic o). I n s u bj ects w h o recei ve t he T D V b o oster or place b o, Visit 
4 a n d Visit 5 will occ ur at 1 m o nt h a n d 6 m o nt hs p ost b o oster, res pecti vel y: Da y 7 5 0 ( M 2 5) a n d 
Da y 9 0 0 ( M 3 0) f or s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o)/ Da y 4 8 0 ( M 1 6) a n d Da y  6 3 0 
( M 2 1) f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States). F or all s u bj ects, Visit 1, Visit 2, 
a n d Visit 3 A/ 3  c orres p o n d t o 2 1 m o nt hs, 3 3 m o nt hs, a n d 3 6 m o nt hs after t he first vacci nati o n i n 
t he pri mar y vacci nati o n series, res pecti vel y. F or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o), 
Visit 3 B, Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 4 5 m o nt hs, 4 6 m o nt hs,  a n d 5 1 m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series, r es pecti vel y. F or s u bj ects fr o m pare nt 
trial D E N-3 0 4 ( U nite d  States), Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 3 7 m o nt hs a n d 
4 2  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series, res pecti vel y . 
6. 1  
T he i ncl usi o n of s u bj ects fr o m ot her trials wit hi n t he T D V pr o gra m ma y be c o nsi dere d if t he y 
meet t he eli gi bilit y criteria f or e ntr y i nt o D E N
3 0 3. D E N -3 0 3 will i ncl u de u p t o 6 0 0 healt h y 
s u bj ects a ge d ≥1 3 t o ≤6 3 years at trial e ntr y. T o e na ble t he assess me nt of a b o oster d ose, t he trial 
will b e d o u ble -bli n de d, ra n d o mize d, a n d place b o -c o ntr olle d fr o m Visit 3 B ( Da y 7 2 0 [ M 2 4])  
o n war ds  f or s u bj ects fr o m par e nt trial D E N 3 1 5 ( Me xic o) a n d fr o m Visit 3 ( Da y 4 5 0 [ M 1 5]) 
o n war ds f or s u bj ects fr o m par e nt trial D E N 3 0 4  ( U nite d States). 
A nti b o d y persiste nce a n d safet y will be assesse d fr o m Visit 1 ( Da y 1 [ M 0]) t hr o u g h Visit 3B 
( Da y 7 2 0 [ M 2 4]) f or u p t o 4 5 ; u p t o 6 3  m o nt hs after t he first vacci nati o n i n t he pri mar y 
vacci nati o n series f or s u bj ects fr o m pare nt trial D E N -3 1 5  ( Me xic o) a n d fr o m Visit 1 
( Da y 1  [ M 0]) t hr o u g h Visit 3 ( Da y 4 5 0 [ M 1 5]) f or u p t o 3 6 m o nt hs after t he first vacci nati o n i n 
t he pri mar y vacci nati o n series f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States).  F urt her 
c haracterizati o n of t he l o n g -ter m h u m oral a n d cell-me diate d i m m u ne res p o nses t o T a ke da’s 
T D V will be u n derta ke n i n a s u bset of a p pr o xi matel y 5 0 v ol u nteers i de ntifie d at e nr oll me nt 
( C MI s u bset: p artici pati o n is o n a v ol u ntar y basis fr o m D E N-3 0 4 o nl y) u p t o Visit 5  ( Da y 6 3 0 
[ M 2 1]). A rete nti o n ph o ne call will be ma de bet wee n Visits 1 a n d 2 o n Da y  1 8 0 ( M 6) t o 
mai ntai n c o ntact wit h t he s u bject/t he s u bj ect’s le gall y acce pta ble re prese ntati ve ( L A R) bet wee n 
site visits a n d t o re mi n d t he s u bj ect/t he s u bj ect’s L A R of a n y u pc o mi n g site visits. At Visit 3 A 
( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 2 ( Da y 3 6 0 [ M 1 2]) f or 
s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States) t he site will disc uss a n y i nf or mati o n t hat is 
perti ne nt t o t he b o oster p hase of t he trial wit h t he s u bj ect. A s ec o n d rete nti o n p h o ne c all will be 
m a de t o s u bjects fr o m p are nt tri al D E N -3 1 5 ( Me xic o) bet wee n Visits 2 a n d 3 o n 
D ay  5 4 0  ( M 1 8). A n a d diti o nal rete nti o n p h o ne call will be ma de t o s u bj ects fr o m pare nt trial 
D E N 3 1 5 ( Me xic o) bet wee n Visit 3 A a n d Visit 3 B o n Da y 6 3 0 ( M 2 1) t o mai ntai n c o ntact wit h 
t he s u bj ect/t he s u bj ect’s L A R bet wee n site visits, a n d t o re mi n d t he s u bj ect/t he s u bj ect’s L A R of 
t he b o oster eli gi bilit y criteria a n d t he u pc o mi n g site visit. Fe male s u bj ects of c hil d beari n g a ge 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 2 9  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
will als o be re mi n de d  of pre g na nc y a v oi da nce g ui da nce a n d acce pta ble met h o ds of c o ntrac e pti o n 
d uri n g t his call.  
At Visit  3 B ( Da y 1 2 6 0 [ M 4 2]) f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 
4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States) , f oll o wi n g all sc he d ule d 
bl o o d dra ws, all s u bj ects will be scree ne d f or ‘ b o oster eli gi bilit y’ t o deter mi ne if t he y are eli gi ble 
t o g o o n t o recei ve t he T D V b o oster i n t he b o oster p hase. A n y s u bj ect w h o fails t o meet t he 
criteria f or ‘ b o oster eli gi bilit y’ wi ll e n d t he trial at Visit 3B ( Da y 1 2 6 0 [ M 4 2]) or Visit 3 ( Da y 
4 5 0 [ M 1 5]), res pecti vel y . All eli gi ble s u bj ects will be ra n d o mize d, usi n g a n i nteracti ve res p o nse 
tec h n ol o g y (I R T) at Visit 3B ( Da y 1 2 6 0 [ M 4 2])/ Visit 3 ( Da y 4 5 0 [ M 1 5]), as a p plica ble,  t o 1 of 2 
trial gr o u ps ( Gr o u p 1 a n d Gr o u p 2) i n a 1: 1 rati o stratifie d b y pare nt trial a n d ser ostat us at 
baseli ne i n t he pare nt trials.  
6. 1  
I m m u n o ge nicit y e val uati o n: 
•  
Ne utra lizi n g a nti b o dies ( b y M N T5 0) will be meas ure d usi n g bl o o d sa m ples c ollecte d fr o m 
all s u bj ects at Visit 1, Visit 2, a n d Visit  3 A/ 3, at Visit 3 B f or s u bj ects fr o m pare nt trial D E N
3 1 5 ( Me xic o) , a n d als o at Visit 4 a n d Visit 5 f or s u bj ects w h o are ra n d o mize d t o Gr o u ps 1 
a n d  2.  
•  
At Visit 3 A/ 3 , a lar ger v ol u me of bl o o d will be c ollecte d fr o m all s u bj ects t o assess 
e x pl orat or y mar kers of t he l o n g -ter m h u m oral i m m u ne res p o nse t o T a ke da’s T D V. 
6. 1  
Safet y e val uati o n:  
•  
Diar y car ds will be distri b ute d t o Gr o u ps 1 a n d 2 at Visit 3 B f or s u bj ects fr o m pare nt trial 
D E N 3 1 5 ( Me xic o)/ Visit 3 f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States)  f or t he 
rec or di n g of: 
6. 1  
Safet y e val uati o n: ... 
•  
M A A Es will be c ollecte d, f or Gr o u ps 1 a n d 2, f oll o wi n g a d mi nistrati o n of t he T D V b o oster 
or place b o fr o m Visit 3 B  t hr o u g h Visit 5 f or s u bj ects fr o m p are nt trial D E N 3 1 5 
( Me xic o)/fr o m Visit 3 t hr o u g h Visit 5 f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d 
States) . M A A Es are defi ne d as A Es lea di n g t o a n u nsc he d ul e d visit t o or b y a healt hcare 
pr ofessi o nal i ncl u di n g visi ts t o a n e mer ge nc y de part me nt, b ut n ot f ulfilli n g seri o us ness 
criteria.  
6. 1  
S u m mar y:  
F or s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o), t he d urati o n of t he c urre nt trial will be 2 4 4 2  
m o nt hs f or s u bj ects w h o fail t o meet t he criteria f or ‘ b o oster eli gi bilit y’ at Visit 3 B  (i ncl usi ve of 
3  4  site visits, a n d  3 bl o o d dra ws) a n d 3 0 4 8  m o nt hs f or al l ot her s u bj ects (i ncl usive of 5 6  site 
visits , a n d 5 6  bl o o d dra ws).  F or s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nite d States), t he trial 
d urati o n will be 1 5 m o nt hs f or s u bj ects w h o fail t o meet t he criteria f or ‘ b o oster eli gi bilit y’ at 
Visit 3 (i ncl usi ve of 3  site visits, 3 bl o o d dra ws) a n d 2 1 m o nt hs f or all ot her s u bj ects (i ncl usi ve 
of 5  site visits, 4  5 bl o o d dra ws).  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 3 0  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
6. 2  
O n g oi n g a n d c C o m plete d p hase 2 trials ha ve e na ble d t he sel ecti o n of t he fi nal T D V f or m ulati o n, 
a d mi nistere d b y S C i nj ecti o n, t hat is use d i n t his st u d y a n d has bee n ta ke n f or war d i n T a ke da’s 
pi v otal de n g ue pr o gra m. T he c urre nt versi o n of t he I B pr o vi des 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.  
I n or der t o mai ntai n t he d o u bl e-bli n d desi g n, f oll o wi n g a d mi nistrati o n of t he T D V b o oster t o 
Gr o u p  1 at Visit  3 B ( Da y 7 2 0 [ M 2 4] ) f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 
( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d  States) , a place b o (sali ne 
s ol uti o n f or i nj ecti o n) will be a d mi nistere d t o Gr o u p 2.  J ustificati o n of t he sa m ple size ( u p t o 
3 0 0  s u bj ects per Gr o u p) is i ncl u de d i n Secti o n 1 3. 3 a n d 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.  
T he ti mi n g of t he pri mar y a n d sec o n dar y e n d p oi nts assessi n g a nti b o d y persiste nce ai ms t o 
pr o vi de data o n persiste nce of t he i m m u ne res p o nse f or ≥3 > 2. 5  years ( 3 2. 7 5  years f or s u bjects 
fr o m pare nt trial D E N-3 0 4 a n d 3. 7 5 5  years f or s u bj ects fr o m pare nt trial D E N -3 1 5) f oll o wi n g 
c o m pleti o n of t he pri mar y vac ci nati o n series.  
6. 3  
F or s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o), t he d urati o n of t he c urre nt trial will be 
2 4 4 2  m o nt hs f or s u bj ects w h o fail t o meet t he criteria f or ‘ b o oster eli gi bilit y’ at Visit 3 B ( Da y 
7 2 0 [ M 2 4] ) a n d 3 0 4 8  m o nt hs f or all ot her s u bj ects (i ncl usi ve of b o oster a d mi nistrati o n at Visit 
3 B [ Da y 7 2 0 ( M 2 4) ] a n d f oll o w-u p t hr o u g h Visit 5  [ Da y 9 0 0 ( M 3 0)]). F or s u bj ects fr o m pare nt 
trial D E N-3 0 4 ( U nite d States), t he trial d urati o n will be 1 5 m o nt hs f or t h ose s u bj ects w h o fail t o 
meet t he criteria f or ‘ b o oster eli gi bilit y’ at Visit 3  ( Da y 4 5 0 [ M 1 5]) a n d 2 1 m o nt hs f or all ot her 
s u bj ects (i ncl usi ve of b o oster ad mi nistrati o n at Visit 3 [ Da y 4 5 0 ( M 1 5)] a n d f oll o w-u p t hr o u g h 
Visit 5 [ Da y 6 3 0 ( M 2 1)]). 
7. 2  
E xcl usi o n Criteri a...  
4.    S u bj ects wit h a pr ol o n ge d peri o d  of ha bitati o n ( ≥1 year) i n a de n g ue e n de mic area wit hi n t he 
2 years pri or t o Visit 1  ( Da y 1 [ M 0]). 
7. 3  
B o oster Eli gi bilit y  
Eli gi bilit y, i ncl u di n g test res ults, m ust t o be c o nfir me d at Visit 3 pri or t o ra n d o mizati o n.  
Assesse d at Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N
3 1 5 ( Me xic o) a n d 
Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N
3 0 4 ( U nite d States). A n y s u bj ect 
w h o meets a n y of t he f ol l o wi n g criteria at Visit 3 will n ot q ualif y f or ra n d o mizati o n t o Gr o u p 1 
or 2 t o recei ve t he T D V b o oster or place b o, res pecti vel y:  
7. 3  
B o oster Eli gi bilit y...  
5.  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 Visit 3 B ( Da y 7 2 0 
[ M 2 4]) f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or 
s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States) ; use of i n hale d, i ntra nasal, or 
t o pical c ortic oster oi ds is 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 Visit 3 B ( Da y 
7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) 
f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States) . 
c) A d mi nistrati o n of i m m u n o gl o b u li 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 a d mi nistrati o n of t he T D V b o oster or place b o at Visit  3 B ( Da y 7 2 0 [ M 2 4]) f or 
s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects 
fr o m pare nt trial D E N-3 0 4 ( U nite d Stat es) ; c o nsi der w het her a p plica ble as a n 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 3 1  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
e xcl usi o n criteri o n or criteri o n f or dela y.  
d)  Recei pt of i m m u n osti m ula nts wit hi n 6 0 da ys pri or t o Visit  3 B ( Da y 7 2 0 [ M 2 4]) f or 
s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects 
fr o m pare nt trial D E N 3 0 4 ( U nite d States) . 
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 Visit  3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N
3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m par e nt trial D E N 3 0 4 ( U nite d 
States) . 
7. 3  
1 3.    Fe male s u bj ects of c hil d -beari n g p ote ntial  w h o are se x uall y acti ve wit h me n, a n d w h o ha ve 
n ot use d a n y of t he acce pta b le c o ntrace pti ve met h o ds f or at least 2 m o nt hs pri or t o Visit 3 B 
( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 
[ M 1 5]) f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d Stat es) . 
a) Of “c hil d beari n g p ote ntial” is defi ne d as stat u s 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 ye ars, stat us after bilateral 
t u bal li gati o n f or at least 1 year, stat us after bilateral o o p h orect o m y, or stat us after 
h ysterect o m y.  
b)  “ Acce pta ble birt h c o ntr ol met h o ds” are defi 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 nj ecti o n, tra ns der mal patc h, i m pla nt, 
cer vical ri n g).  
II. 
B arrier met h o d (c o n d o m wit h s per mici de or dia p hra g m wit h s per mici de) e ver y 
ti me d uri n g i nterc o urse. 
III. 
Intra uteri ne de vice (I U D).  
I V. 
M o n o ga m o us relati o ns hi p wit h a  vasect o mize d part ner. P art ner m ust ha ve bee n 
vasect o mize d f or at least si x6  m o nt hs pri or t o Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or 
s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or 
s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States) . 
1 4.    Fe male s u bj ects 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” f or u p t o 6 wee ks after a d mi nistrati o n of t he 
T D V  b o oster or place b o at  Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N -
3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m par e nt trial D E N -3 0 4 ( U nite d 
States) . 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 or breastfee d d uri n g t his 
peri o d.  
8. 1  
T he i n vesti gati o nal vacci ne is T a ke da’s T D V , a tetra vale nt vacci ne c o m prise d of 1 m olec ul arl y 
c haracterize d, atte n uate d de n g ue vir us strai n ( T D V -2), a n d 3 rec o m bi na nt c hi meric de n g ue vir us 
strai ns ( T D V-1, T D V -3, a n d 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.  
8. 1. 1  
T he s p o ns or will s u p pl y st u d y sites wit h T D V, T D V dil ue nt, a n d place b o pac ka ge d i nt o si n gle 
d ose dis pe nsi n g cart o ns. T he cart o ns will be la bele d i n a n  u n bli n de d fas hi o n t hata n d  will 
c o ntai n p erti ne nt trial i nf or mati o n a n d ca uti o n state me nts i n l ocal la n g ua ges. T D V or place b o 
will b e dis pe nse d i n a bli n de d ma n ner b y I R T. Receivi n g , st or a ge, acc o u nt a bility, a n d 
dis pe nsi n g of  u n bli n de d tri al v acci nes s h o ul d o nly be perf or m e d by u n bli n de d pers o n nel  (see 
Secti o n s 8. 2  a n d 8. 4)  t o e ns ure t h at t he tri al bli n d is n ot br o ke n. F urt her details ca n be f o u n d i n 
t he P har mac y Ma n ual. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 3 2  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
8. 1. 3  
T he  T trial vacci ne d oses t hat will be pr o vi de d t o eac h trial gr o u p at Visit 3 B ( Da y 7 2 0 [ M 2 4] ) 
f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m 
pare nt trial D E N -3 0 4 ( U nite d States)  are prese nte d i n T a ble 8.a.  
8. 1. 3  
 
a   D ay 1 2 6 0 ( M 4 2) f or s u bjects fr o m p are nt tri al D E N -3 1 5 ( Me xic o) a n d D ay 4 5 0 ( M 1 5) f or  
s u bjects fr o m p are nt tri al D E N-3 0 4 ( U nite d St ates).  
8. 2  
T he desi g nee will use I R T a gai n at ra n d o mizati o n (Visit  3 B [ Da y 7 2 0 ( M 2 4)] f or s u bj ects fr o m 
pare nt trial D E N -3 1 5 [ Me xic o]/ Visit 3 [ Da y 4 5 0 ( M 1 5)] f or s u bj ects fr o m pare nt trial D E N-3 0 4 
[ U nite d States] ) o n t he da y of T D V b o oster or place b o a d mi nistrati o n ( Visit 3) t o pr o vi de t he 
vacci nati o n i de ntificati o n n u m ber f or t he vacci ne d ose . 
T he tri al v acci ne ( T D V b o oster/ pl ace b o) will be a d mi nistere d o nly by u n bli n de d pers o n nel 
w h o are q u alifie d t o perf or m t h at f u ncti o n u n der a p plic a ble l a ws a n d re g ul ati o ns f or t h at 
s pecific tri al. T he bli n de d 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 t he trial vacci ne ( T D V b o oster/ place b o) t o s u bj ects e nr olle d i n t he trial 
accor 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 trial vacci ne ( T D V 
b o oster/ place b o) will be a d mi nistere d o nl y b y u n bli n de d pers o n nel w h o are q ualifie 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 ulati o ns f or t hat s pecific trial. 
8. 2. 1  
Pri or t o T D V b o oster or place b o vacci nati o n, a s u bj ect m ust be deter mi ne d t o be eli gi ble a n d it 
m ust b e dee me d cli nicall y a p pr o priate i n t he j u d g me nt of t he i n vesti gat or t o a d mi nister t he 
b o oster d ose. Eli gi bilit y f or tri al e ntr y is e val uate d acc or di n g t o t he i ncl usi o n a n d e xcl usi o n 
criteria f or e ntr y o utli ne d i n t his pr ot oc ol ( Secti o n  7. 1 a n d Secti o n  7. 2). Pri or t o T D V b o oster or 
place b o a d mi nistrati o n at Vis it 3B ( Da y 7 2 0 [ M 2 4] ) f or s u bjects fr o m pare nt trial D E N-3 1 5 
( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States) , site 
staff m ust d eter mi ne if t he s u bj ect is eli gi ble t o recei ve t he T D V b o oster d ose b y e val uati n g t he 
criteria f or ‘ b o oster eli gi bilit y’ o utli ne d i n Secti o n 7. 3.  
Sta n dar d i m m u nizati o n practi ces are t o be 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 nj ecti o n b y t he S C 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  [1 6 1 7 ]. 
8. 4  
T he trial will be c o n d ucte d i n a d o u ble -bli n d ma n ner fr o m Visit 3 B ( Da y 7 2 0 [ M 2 4]) o n war ds 
f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) o n war ds f or s u bj ects 
fr o m pare nt trial D E N 3 0 4 ( U nite d States) , mea ni n g t hat fr o m t his p oi nt o n war ds t he s u bj ect, 
t h ose res p o nsi ble f or t he e val uati o n of a n y trial e n d p oi nt, a n d t he s p o ns or will all be u na ware of 
w het her t he T D V b o oster or place b o was a d mi nistere d.  
8. 5  
T he trial vacci ne bli n d, w hic h will be i n place fr o m ra n d o mi zati o n at Visit 3  ( Da y 4 5 0 [ M 1 5]), 
s hall n ot b e br o ke n b y t he i n vesti gat or u nless i nf or mati o n c o ncer ni n g t he T D V b o oster or 
place b o is necessar y f or t he me dical treat me nt of a s u bj ect, or i n cases of pre g na nc y if a tri al 
s u bj ect re q uests it. 
9. 0  
N ote t hat t he ti mi n g of Visit 1, Visit 2, a n d Visit 3 A/ 3  will b e t he sa me f or all s u bj ects 
( Da y 1  [ M 0], Da y 3 6 0 [ M 1 2], a n d Da y 4 5 0 [ M 1 5], res pecti vel y), b ut f or o perati o nal reas o ns, 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 3 3  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
a d mi nistr ati o n of t he b o oster d ose will be dela ye d u ntil Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects 
fr o m pare nt trial D E N 3 1 5 ( Me xic o). I n s u bj ects w h o recei ve t he T D V b o oster or place b o, Visit 
4 a n d Visit 5 will occ ur at 1 m o nt h a n d 6 m o nt hs p ost b o oster, res pecti vel y:  Da y 7 5 0 ( M 2 5) a n d 
Da y 9 0 0 ( M 3 0) f or s u bj ects fr o m pare nt trial D E N
3 1 5 ( Me xic o)/ Da y 4 8 0 ( M 1 6) a n d Da y 6 3 0 
( M 2 1) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States). F or all s u bj ects, Visit 1, Visit 2, 
a n d Visit 3 A/ 3  c orres p o n d t o 2 1 m o nt hs, 3 3 m o nt hs, a n d 3 6 m o nt hs after t he first vacci nati o n i n 
t he pri mar y vacci nati o n series, res pecti vel y. F or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o), 
Visit 3 B, Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 4 5 m o nt hs, 4 6 m o nt hs a n d 5 1 m o nt hs 
after t he first vacci n ati o n i n t he pri mar y vacci nati o n series, r es pecti vel y. F or s u bj ects fr o m pare nt 
trial D E N 3 0 4 ( U nite d States), Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 3 7 m o nt hs a n d 
4 2  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series, res pecti v el y.  
N ote, f or all s u bjects Visit 1 ( D ay 1 [ M 0]) a n d Visit 2 ( D ay 3 6 0 [ M 1 2]) c orres p o n d t o 
2 1  m o nt hs a n d 3 3 m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series i n t he 
p are nt tri al. F or s u bjects fr o m p are nt tri al D E N -3 1 5 ( Me xic o), Visit 3 ( D ay 1 2 6 0 [ M 4 2]), Visit 
4 ( D ay 1 2 9 0 [ M 4 3]), a n d Visit 5 ( D ay 1 4 4 0 [ M 4 8 ]) i n t his tri al c orres p o n d t o 6 3 m o nt hs, 6 4 
m o nt hs, a n d 6 9  m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series, 
res pectively. F or s u bjects fr o m p are nt tri al D E N-3 0 4 ( U ni te d St ates), Visit 3 ( D ay 4 5 0 [ M 1 5]), 
Visit 4 ( D ay 4 8 0 [ M 1 6]), a n d Visit 5 ( D ay 6 3 0 [ M 2 1]) i n t his tri al c orres p o n d t o 3 6 m o nt hs, 
3 7  m o nt hs, a n d 4 2 m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series i n t he 
p are nt tri al, res pectively.  
9. 1. 1  
A s u bset of 5 0 v ol u nteers ( D E N -3 0 4 o nl y) will be assi g ne d t o t he C MI s u bset at trial e ntr y t o 
per mit a m ore detaile d c haracterizati o n of t he l o n g -ter m h u m oral a nd cell -me diate d i m m u ne 
res p o nse t o T a ke d a’s T D V (u p t o Visit 5 : [ Da y 9 0 0 ( M 3 0)] f or s u bj ects fr o m pare nt trial 
D E N -3 1 5 [ Me xic o] a n d [ Da y 6 3 0 ( M 2 1)] f or s u bj ects fr o m pare nt trial D E N -3 0 4 [ U nite d 
States] ). 
D ue t o c ha n ges i n t he trial desi g n i n Me xic o (pr ot oc ol a me n d me nt 1, date d 0 9 Marc h 2 0 2 0 a n d 
pr ot oc ol a me n d me nt 2, date d 2 2 Fe br uar y 2 0 2 1 pr ot oc ol a me n d m e nt 3 , d ate d 2 2  A u g ust  2 0 2 2 ), 
all s u bj ects fr o m p are nt tri al D E N-3 1 5 ( Me xic o) will n o w be as ke d t o re -c o nse nt usi n g a n  
u p date d i nf or me d c o nse nt f or m (s) (I C F) or a n u p date d i nf or me d c o nse nt a n d pe diatric asse nt 
f or ms, as a p plic a ble, at Visit 2 ( Da y 3 6 0 [ M 1 2]) Visit 3  or at t he ne xt site visit if Visit 2 has 
passe d  bef ore a n y f urt her pr ot oc ol -directe d pr oce d ures are perf or me d . 
9. 1. 2  
De m o gra p hic i nf or mati o n t o be o btai ne d at Visit 1 ( Da y 1 [ M 0]) will i ncl u de a ge/ date of birt h, 
se x, race, a n d et h nicit y as des cri be d b y t he s u bj ect or s u bj ect’s L A R.  
A me dical hist or y  u p date will be c ollecte d at e nr oll me nt ( Visit 1  [ Da y 1 ( M 0)]) a n d after 
ra n d o mizati o n i n s u bj ects t hat are eli gi ble f or T D V b o oster or place b o a d mi nistr ati o n at Visit 
3 B ( Da y 7 2 0 [ M 2 4] ) f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5 ]) 
f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States) . 
9. 1. 2  
Me dical hist or y (i ncl u di n g c orres p o n di n g me dicati o n) t o be o btai ne d at Visit 1  ( Da y 1 [ M 0]) 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. Me dic al hist or y u p date (i ncl u di n g 
c orres p o n di n g me dicati o n) t o be o btai ne d pri or t o b o oster a d mi nistr ati o n at Visit 3 B ( Da y 7 2 0 
[ M 2 4]) f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bjects 
fr o m pare nt trial D E N-3 0 4 ( U nite d States)  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 bet wee n V isit 1 ( Da y 1 [ M 0]) a n d Visit 3 B ( Da y 7 2 0 [ M 2 4 ]/ Visit 3 
( Da y 4 5 0 [ M 1 5]), as a p plica ble. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 3 4  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
9. 1. 2  
All me dicati o ns, vacci nes a n d bl o o d pr o d ucts ta ke n or recei ve d b y t he s u bj ects are t o be assesse d 
a n d c ollecte d as Pri or or C o nc o mita nt Me dicati o ns a n d rec or de d i n t he s u bj ect’s s o urce 
d oc u me nt a n d e C R F as f oll o ws:  
a) 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 t he T D V 
b o oster or place b o at Visit  3 B ( Da y 7 2 0 [ M 2 4] ) f or s u bj ects fr o m pare nt trial D E N-3 1 5 
( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d 
States)  a n d u p t o 1 m o nt h ( mi ni m u m 2 8 da ys) t hereafter.  
b)  Vacci nes: fr o m 1 m o nt h ( mi ni m u m 2 8 da ys) pri or t o a n y bl o o d sa m ple c ollecti o n or 
a d mi nistrati o n of t he T D V b o oster/ place b o at Visit 3 B ( Da y 7 2 0 [ M 2 4] ) f or s u bj ects 
fr o m pare nt trial D E N -3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt 
trial D E N-3 0 4 ( U nite d States)  a n d u p t o 1  m o nt h ( mi ni m u m 2 8 da ys) t hereafter.  
c) Bl o o d pr o d ucts a n d i m m u n o gl o b uli ns: wit hi n 3 m o nt hs pri or t o a d mi nistrati o n of t he 
T D V b o oster or place b o at Vis it 3B ( Da y 7 2 0 [ M 2 4] ) f or s u bj ects fr o m pare nt trial 
D E N -3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N -3 0 4 
( U nite d States). 
d)  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 Visit 3 B ( Da y 7 2 0 [ M 2 4] ) f or 
s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects 
fr o m pare nt trial D E N-3 0 4 ( U nite d States) . 
e) I m m u n os u p pressi ve t hera pies: wit hi n 6 m o nt hs pri or t o Visit 3B ( Da y 7 2 0 [ M 2 4] ) f or 
s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y  4 5 0 [ M 1 5]) f or  s u bj ects 
fr o m pare nt trial D E N-3 0 4 ( U nite d States) . 
9. 1. 2  
Pr o hi bite d t hera pies ( Refer t o Secti o ns 7. 2 a n d 7. 3):  
a) 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 
i ncl u di n g de n g ue ( ot her t ha n T a ke da’s T D V), Y F, J E vir uses or tic k-b or ne 
e nce p halitis.  
b)  A n y ot her vacci nes wit hi n t he 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 a n y bl o o d sa m ple c ollecti o n or T D V  b o oster/ place b o a d mi nistrati o n 
at Visit 3 B ( Da y 7 2 0 [ M 2 4] ) f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 
( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States) . 
c) 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 Visit  3 B ( Da y 7 2 0 
[ M 2 4]) f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or 
s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States) ; use of i n hale d, i ntra nasal, or 
t o pical c ortic oster oi ds is all o we d. 
d)  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 Visit 3 B ( Da y 
7 2 0 [ M 2 4] ) f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) 
f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States) . 
e) 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 a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3 B ( Da y 7 2 0 [ M 2 4] ) f or 
s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y  4 5 0 [ M 1 5]) f or s u bj ects 
fr o m pare nt trial D E N 3 0 4 ( U nite d States) . 
f) 
Recei pt of i m m u n osti m ula nts wit hi n 6 0 da ys pri or t o Visit 3 B ( Da y 7 2 0 [ M 2 4] ) f or 
s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects 
fr o m pare nt trial D E N 3 0 4 ( U nite d States) . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 3 5  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
g)  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 Visit 3 B ( Da y 7 2 0 [ M 2 4] ) f or s u bj ects fr o m pare nt trial 
D E N 3 1 5 ( Me x ic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 
( U nite d States). 
9. 1. 3  
O nl y s u bj ects w h o meet t he criteria f or ‘ b o oster eli gi bilit y’ at Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or 
s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt 
trial D E N-3 0 4 ( U nite d States)  are eli gi ble f or ra n d o mizati o n i nt o t he b o oster p hase . 
9. 1. 3  
If t he s u bj ect is i neli gi ble f or ra n d o mizati o n at Visit 3,B ( Da y 7 2 0 [ M 2 4])/ Visit 3 ( Da y 4 5 0 
[ M 1 5]), as a p plica ble, the y will e n d t he trial at t his p oi nt a n d t he i n vesti gat or s h o ul d rec or d t h e 
pri mar y reas o n f or n o n -ra n d o mizati o n i n t he s u bj ect’s s o urce d oc u me nts a n d e C R F. 
9. 1. 4  
A c o m plete p h ysical e xa m will be perf or me d i n all s u bj ects at Visit 1 ( Da y 1 [ M 0]) a n d i n 
s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 at Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt 
trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nite d 
States)  acc or di n g t o t he i n vesti gat or’s sta n dar d pr actice. 
9. 1. 4  
S u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 will als o u n der g o a t ar gete d s y m pt o m -directe d p h ysical 
e xa mi nati o n at Visit 4 (Da y 7 5 0 [ M 2 5]  f or s u bj ects fr o m pare nt trial D E N 3 1 5 [ Me xic o]/ Da y 
4 8 0 [ M 1 6 ] f or s u bj ects fr o m pare nt trial D E N 3 0 4 [ U nite d States]) a n d Visit 5  (Da y 9 0 0 [ M 3 0]  
f or s u bj ects fr o m pare nt trial D E N 3 1 5 [ Me xic o]/ Da y 6 3 0 [ M 2 1] f or s u bj ects fr o m pare nt trial 
D E N 3 0 4 [ U nite d States]) . A n y cli nicall y si g nifica nt c ha n ges fr o m t he baseli ne  e xa mi nati o n 
perf or me d at Visit 1 ( Da y 1 [ M 0]) 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. 
9. 1. 5  
F or s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o), vital si g ns will be meas ure d i n all s u bj ects at 
Visit 1 ( Da y 1 [ M 0]), Visit 2 ( Da y 3 6 0 [ M 1 2]), Visit 3 A ( Da y 4 5 0 [ M 1 5]), a n d Visit 3 B 
( Da y 7 2 0 [ M 2 4]), a n d i n t h ose s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 at Visit 4 ( Da y 7 5 0 
[ M 2 5]) a n d Visit 5 ( Da y 9 0 0 [ M 3 0]).  F or s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nite d Stat es),  
v V it al si g ns will be meas ure d i n all s u bj ects at Visit 1 ( Da y 1 [ M 0]), Visit 2 ( Da y 3 6 0 [ M 1 2]), 
a n d Visit 3  ( Da y 4 5 0 [ M 1 5]), a n d i n t h ose s u bj ects ra n d o mi ze d t o Gr o u ps 1 a n d 2 at Visit 4 (Da y 
4 8 0 [ M 1 6]  a n d Visit 5  ( Da y 6 3 0 [ M 2 1]). T hese 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, heart rate, a n d b o d y 
te m perat ure. 
9. 1. 6  
F or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o), b B l o o d sa m ples f or i m m u n o ge nicit y 
assess me nts will be c ollecte d fr o m all s u bj ects ( 1 0 m L) at Visit 1  ( Da y 1 [ M 0]), Visit 2 ( Da y 3 6 0 
[ M 1 2]), Visit 3 A ( Da y 4 5 0 [ M 1 5], a n d Visit 3 B ( Da y 7 2 0 [ M 2 4]) , a n d fr o m t h ose s u bj ects 
ra n d o mize d t o Gr o u ps 1 a n d 2 at Visit 4 ( Da y 7 5 0 [ M 2 5]) a n d Visit 5  ( Da y 9 0 0 [ M 3 0]). F or 
s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States), bl o o d sa m ples f or i m m u n o ge nicit y 
assess me nts will be c ollecte d fr o m al l s u bj ects ( 1 0 m L) at Visit 1 ( Da y 1 [ M 0]), Visit 2 ( Da y 3 6 0 
[ M 1 2]), a n d Visit 3 ( Da y 4 5 0 [ M 1 5] a n d fr o m t h ose s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 at 
Visit 4 ( Da y 4 8 0 [ M 1 6]) a n d Visit 5 ( Da y 6 3 0 [ M 2 1]).  
A lar ger bl o o d sa m ple ( 4 0  m L) will als o be c ollecte d fr o m all s u bj ects t o assess e x pl orat or y 
mar kers of t he l o n g -ter m h u m oral i m m u ne res p o nse t o T a ke da’s T D V at Visit 3A/ 3 ( Da y 4 5 0 
[ M 1 5]), pri or t o T D V b o oster or place b o a d mi nistrati o n f or s u bj ects ra n d o mize d t o Gr o u ps 1 
a n d  2.  
A p plica ble o nl y t o s u bj ects fr o m pare nt trial D E N-3 0 4 [ U nite d States]: A d diti o nal bl o o d sa m ples 
(4 0 -5 0 m L) will be c ollecte d fr o m s u bj ects i n t he C MI s u bset t o all o w f urt her c haracterizati o n of 
t he l o n g-ter m h u m oral a n d cell-me diate d i m m u ne res p o nses t o T a ke da’s T D V at Visit 1  ( Da y 1  
[ M 0]), Visit 2 ( Da y 3 6 0 [ M 1 2]) a n d Visit 3 , ( Da y 4 5 0 [ M 1 5]) a n d i n s u bj ects ra n d o mize d t o 
Gr o u ps 1 a n d 2 at Visit 4  ( Da y 4 8 0 [ M 1 6]) a n d Visit 5  ( Da y 6 3 0 [ M 2 1]). 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 3 6  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
F or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o), t he ma xi m u m v ol u me of bl o o d ta ke n at a n y 
si n gle visit is a p pr o xi matel y 5 0 m L. T he t otal v ol u me of bl o o d c ollecte d f or t he trial d urati o n is 
a p pr o xi matel y 8 0 1 0 0 m L.  
F or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States), t T he ma xi m u m v ol u me of bl o o d ta ke n at 
a n y si n gle visit is a p pr o xi matel y 9 0 m L f o r s u bj ects i n t he C MI s u bset a n d a p pr o xi matel y 5 0 m L 
f or all ot her s u bj ects. T he t otal v ol u me of bl o o d c ollecte d f or t he trial d urati o n is a p pr o xi matel y 
1 9 0 -3 1 0 m L f or s u bj ects i n t he C MI s u bset a n d a p pr o xi matel y 7 0 -9 0 m L f or all ot her s u bj ects.  
9. 1. 8  
Safet y assess me nts will i ncl u d e t he c ollecti o n a n d rec or di n g of s olicite d l ocal (i nj ecti o n sit e) a n d 
s yste mic A Es, u ns olicite d A Es, A Es (seri o us a n d n o n -seri o us), pre g na ncies, a n d M A A Es fr o m 
Visit  3 B ( Da y 7 2 0 [ M 2 4] ) o n war ds f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/fr o m Visit 
3 ( Da y 4 5 0 [ M 1 5]) o n war ds f or s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nite d States) ra n d o mize d 
t o Gr o u ps 1 a n d 2 f oll o wi n g a dmi nistrati o n of t he b o oster d ose or place b o, res pecti vel y . 
9. 1. 9  
F or fe male s u bj ects of c hil d beari n g p ote ntial, pre g na nc y testi n g ( uri ne) will be perf or me d pri or 
t o a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3B ( Da y 7 2 0 [ M 2 4] ) f or s u bj ects fr o m 
pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 
( U nite d States). Res ults m ust be c o nfir me d a n d d oc u me nte d as ne gati ve pri or t o a d mi nistr ati o n 
of t he T D V b o oster or place b o at Visit 3 B ( Da y 7 2 0 [ M 2 4] )/ Visit 3 ( Da y 4 5 0 [ M 1 5]), as 
a p plica ble . 
9. 1. 9  
Fe male s u bj ects of c hil d -beari n g p ote ntial  w h o are se x uall y acti ve wit h me n, are a d vise d t o use 
a n acce pta ble c o ntrace pti ve met h o d f or at least 2 m o nt hs pri or t o Visit 3 B ( Da y  7 2 0 [ M 2 4]) f or 
s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt 
trial D E N -3 0 4 ( U nite d States) . S u bj ects will be pr o vi de d wit h i nf or mati o n o n acce pta ble 
met h o ds of c o ntrace pti o n as p art of t he s u bj ect 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 nse nt f or m at Visit 1 ( Da y 1 [ M 0]) stati n g t hat t he y u n dersta n d t he req 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. F urt her g ui da n ce wit h res pect t o t he a v oi da nce of 
pre g na nc y will be pr o vi de d t o all s u bj ects of c hil d beari n g p ote ntial at Visit 3 A ( Da y  4 5 0 [ M 1 5]) 
f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Vi sit 2, ( Da y 3 6 0 [ M 1 2]) f or s u bj ects fr o m 
pare nt trial D E N -3 0 4 ( U nite d States) a n d t o all s u bj ects of c hil d beari n g p ote ntial ra n d o mi ze d t o 
Gr o u p 1 or 2 at Visit 3 B ( Da y  7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o)/ Visit 
3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nite d States), as part of t he trial 
pr oce d ures ( Secti o n 2. 1). Fe males of c hil d beari n g p ote ntial , w h o are ra n d o mize d t o Gr o u p 1 or 2 
a n d are se x uall y acti ve, m ust als o be re mi n de d at Visit 3 B ( Da y  7 2 0 [ M 2 4])/ Visit 3 ( Da y 4 5 0 
[ M 1 5]) a n d at Visit 4 ( Da y 7 5 0 [ M 2 5] f or s u bj ects fr o m pare nt trial D E N-3 1 5 [ Me xic o]/ Da y 4 8 0 
[ M 1 6] f or s u bj ects fr o m pare nt trial D E N-3 0 4 [ U nite d States]) t o a d here t o acce pta ble 
c o ntrace pti ve met h o ds f or u p t o 6 wee ks after T D V b o oster or place b o a d mi nistrati o n; t he y will 
als o be a d vise d n ot t o d o nate o va or breastfee d d uri n g t his p eri o d.  
9. 1. 9  
( d)     M o n o ga m o us relati o ns hi p wit h a  vasect o mize d part ner. P art ne r m ust ha ve bee n 
vasect o mize d f or at least si x6  m o nt hs pri or t o Visit 3 B ( Da y 7 2 0 [ M 2 4] ) f or s u bj ects fr o m 
pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial 
D E N 3 0 4 ( U nite d States) . 
9. 1. 1 1  
9. 1. 1 1   D oc u me nt ati o n of S u bjects W h o Are N ot C o nsi de re d Eli gi ble f or Tri al E ntr y 
( Visit 1  [ D a y 1 ( M 0)]) or R a n d o miz ati o n ( Visit 3 B [ D a y 7 2 0 ( M 2 4)] f or S u bjects 
fr o m P are nt Tri al D E N 3 1 5 [ M e x ic o]/ Visit 3 [ D a y 4 5 0 ( M 1 5)] f or S u bjects fr o m 
P are nt Tri al D E N 3 0 4 [ U nite d St ates] ) 
I n vesti gat ors m ust acc o u nt f or all s u bj ects w h o si g n a n i nf or me d c o nse nt or w h o ha ve a si g ne d 
pe diatric asse nt f or m. If t he s u bj ect is n ot eli gi ble f or trial e ntr y at Visit 1 ( Da y 1 [ M 0]) or f or 
ra n d o mizati o n t o recei ve t he T D V b o oster or place b o at Visit 3 B ( Da y 7 2 0 [ M 2 4] ) f or s u bjects 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 3 7  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial 
D E N 3 0 4 ( U nite d States) , 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 de nial of trial e ntr y (at Visit  1  [ Da y 1 ( M 0)]) or n o n-ra n d o mizati o n (at 
Visit 3 B [ Da y 7 2 0 ( M 2 4) ]/ Visit 3 [ Da y 4 5 0 ( M 1 5)]) is t o be rec or de d i n t he e C R F usi n g t he 
f oll o wi n g cate g ories: 
9. 3. 1  
9. 3 . 1    Site Visits Pri or t o T D V B o oster or Pl ace b o A d mi nistr ati o n ( Visit 1  [ D a y 1 ( M 0)] 
a n d Visit 2  [ D a y 3 6 0 ( M 1 2)]  All S u bjects, a n d Visit 3 A [ D a y 4 5 0 ( M 1 5)] 
 
A p plic a ble t o S u bjects fr o m P are nt Tri al D E N
3 1 5 [ M e xic o] O nl y ) 
Site visits t hat occ ur pri or t o a d mi nistrati o n of t he T D V b o oster or place b o a n d d o n ot i ncl u de a 
vacci nati o n will b e perf or me d at Visit 1 ( Da y 1 [ M 0]) a n d Visit 2  ( Da y 3 6 0 [ M 1 2]). 
A d diti o nal pr oce d ures t o be perf or me d at Visit 1  ( Da y 1 [ M 0]): 
9. 3. 1  
Pr oce d ures t o be perf or me d at Visit 1 ( Da y 1 [ M 0]) a n d Visit 2 ( Da y 3 6 0 [ M 1 2]) i ncl u de: 
1.    B ef ore perf or mi n g a n y tri al pr oce d ure, a n i nf or me d c o nse nt f or mI C F or i nf or me d c o nse nt 
a n d pe diatric asse nt f or m m ust be si g ne d. Refer t o Secti o n 9. 1. 1.  
9. 3. 1  
A d diti o nal pr ocesses t o be c o m plete d at Visit 2 ( Da y 3 6 0 [ M 1 2]):  
1.  B ef ore p erf or mi n g a n y f urt her pr ot oc ol -directe d pr oce d ures, all sites s h o ul d as k s u bj ects t o 
re-c o nse nt usi n g t he u p date d i nf or me d c o nse nt f or m(s) or u p date d i nf or me d c o nse nt a n d 
pe diatric asse nt f or ms c orres p o n di n g t o pr ot oc ol a me n d me nt 1, date d 0 9 Marc h 2 0 2 0 a n d  
pr ot oc ol a me n d me nt 2, date d 2 2 Fe br uar y 2 0 2 1. A n  oral s u m mar y of a n y maj or c ha n ges t hat 
ha ve bee n ma d e t o t he st u d y s h o ul d be pr o vi de d t o t he s u bj ect a n d t he s u bj ect’s L A R w her e 
a p plica ble i n a d diti o n t o t he I C F/ Asse nt F or m. U p o n c o m pl eti o n, t his pr ocess s h o ul d be 
d oc u me nte d i n t he me dical c hart as part of t he re -c o nse nt pr ocess. Re -c o nse nt date s h o ul d 
als o be d oc u me nte d i n t he ele ctr o nic Case Re p ort F or m (e C R F). If Visit 2 has passe d, 
re-c o nse nt will o cc ur at t he ne xt site Visit. Refer t o Secti o n 9. 1. 1.  
P r oce d ures t o be perf or me d at Visit 3 A ( Da y 4 5 0 [ M 1 5])  s u bj ects fr o m pare nt trial D E N-3 1 5 
( Me xic o) o nl y, i ncl u de: 
1.  B ef ore perf or mi n g a n y f urt her pr ot oc ol -directe d pr oce d ures, all sites s h o ul d c hec k t hat t he 
s u bj ect has re-c o nse nte d usi n g t he u p date d i nf or m e d c o nse nt f or m(s) or u p date d i nf or me d 
c o nse nt a n d pe diatric asse nt f or ms c orres p o n di n g t o pr ot oc ol a me n d me nt 1, date d 0 9 Marc h 
2 0 2 0 a n d pr ot oc ol a me n d me nt 2, date d 2 2 Fe br uar y 2 0 2 1. Refer t o Secti o n 9. 1. 1  f or details. 
2.  C o nc o mita nt vacci nati o n u p date.  
3.  C hec k  vital si g ns. Refer t o Se cti o n  9. 1. 5 . 
4.  C ollect a n d rec or d a n y S A Es a n d a n y A Es lea di n g s u bj ect disc o nti n uati o n or wit h dra wal. 
Refer t o Secti o ns 1 0. 4. 4  a n d  1 0. 4. 1 . 
5.  C hec k t hat t he s u bj ect d oes n ot meet a n y of t he criteria f or dela y of bl o o d sa m pli n g. Refer t o  
Secti o n 7. 4.  
6.  C ollect a bl o o d sa m ple fr o m all s u bj ects ( o ne a d diti o nal 4 0 m L bl o o d sa m ple s h o ul d be als o 
c ollecte d fr o m s u bj ects i n t he C MI s u bset). Bl o o d s h o ul d be ta ke n fr o m s u bj ects usi n g a n 
ase ptic ve ni p u nct ure tec h ni q ue f or ser ol o gical i m m u n o ge nicit y testi n g. Refer t o 
Secti o ns  9. 1. 6  a n d  9. 1. 7 . 
9. 3. 2  
9. 3. 2    Pre -V acci n ati o n Pr oce d ures ( Visit  3 B [ D a y 7 2 0 ( M 2 4)] f or S u bjects fr o m P ar e nt 
Tri al D E N 3 1 5 [ M e xic o]/ Vis it 3 [ D a y 4 5 0 ( M 1 5)] f or S u bjects fr o m P are nt Tri al 
D E N 3 0 4 [ U nite d St ates] ) 
B ef ore perf or mi n g a n y f urt her pr ot oc ol -directe d pr oce d ures, all sites i n Me xic o s h o ul d c he c k 
t hat t he s u bj ect has re-c o nse nt e d usi n g t he u p date d i nf or me d c o nse nt f or m(s)I C F or a n u p date d 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 3 8  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
i nf or me d c o nse nt a n d pe diatric asse nt f or ms, as a p plic a ble, c orres p o n di n g t o pr ot oc ol 
a me n d me nt 1, date d 0 9 Marc h 2 0 2 0 a n d pr ot oc ol a me n d me nt 2, date d 2 2 Fe br uar y 2 0 2 1 pr ot oc ol 
a m e n d m e nt 3, d ate d 2 2 A u g ust 2 0 2 2 . Refer t o Secti o n 9. 1. 1 f or details.  
P ri or t o a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects 
fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial 
D E N 3 0 4 ( U nite d States)  t he f oll o wi n g pr oce d ures will be u n derta ke n: 
9. 3. 2  
5.    Re vie w t he criteria f or ‘ b o oster eli gi bilit y’. Refer t o Se cti o n 7. 3.  
a. 
A n y s u bj ect w h o fails t o meet t he criteria f or ‘ b o oster eli gi bilit y’ will e n d t he tr ial 
f oll o wi n g bl o o d sa m ple c ollecti o n(s) at Visit 3B ( Da y 7 2 0 [ M 2 4])/ Visit 3 ( Da y 4 5 0 
[ M 1 5]), as a p plica ble. Refer t o Secti o n 9. 3. 7.  
9. 3. 3  
9. 3. 3    V acci n ati o n Pr oce d ures ( Visit 3 B [ D a y 7 2 0 ( M 2 4)] f or S u bjects fr o m P are nt Tri al 
D E N 3 1 5 [ M e xic o]/ Visit 3 [ D a y 4 5 0 ( M 1 5)] f or S u bjects fr o m P are nt Tri al D E N 3 0 4 
[ U nite d St ates]) 
Vacci nati o n pr oce d ures will o nl y be perf or me d f or s u bj ects w h o meet t he criteria f or ‘ b o oster 
eli gi bilit y’ ( Secti o n 7. 3) at Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects fr o m pare nt trial D E N 3 1 5 
( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States)  a n d 
are ra n d o mize d t o Gr o u ps 1 ( T D V) a n d 2 ( place b o) : 
9. 3. 4  
9. 3. 4     P ost -V acci n ati o n Pr oce d ures ( Visit 3 B [ D a y 7 2 0 ( M 2 4)] f or S u bjects fr o m P ar e nt 
Tri al D E N 3 1 5 [ M e xic o]/ Visit 3 [ D a y 4 5 0 ( M 1 5)] f or S u bjects fr o m P are nt Tri al 
D E N 3 0 4 [ U nite d St ates] ) 
T he f oll o wi n g p ost -vacci nati o n pr oce d ures will be perf or me d at Visit  3 B ( Da y 7 2 0 [ M 2 4]) f or 
s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( D a y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt 
trial D E N-3 0 4 ( U nite d States) : 
9. 3. 4  
4.    T he site s h o ul d sc he d ule t he ne xt trial visit ( Visit 4: Da y 7 5 0 [ M 2 5]  f or s u bj ects fr o m pare nt 
trial D E N 3 1 5 [ Me xic o]/ Da y 4 8 0 [ M 1 6]  f or s u bj ects fr o m pare nt trial D E N 3 0 4 [ U nite d 
States] ) wit h t he s u bj ect or s u bj ect’s L A R. 
9. 3. 4  
T he s u bj ect or t he s u bj ect’s L A R will recei ve a writte n re mi n der of t he ne xt pla n ne d trial a cti vit y 
( Visit 4: Da y 7 5 0 [ M 2 5]  f or s u bj ects fr o m pare nt trial D E N-3 1 5 [ Me xic o]/ Da y 4 8 0 [ M 1 6]  f or 
s u bj ects fr o m pare nt trial D E N-3 0 4 [ U nite d States] ). 
9. 3. 5  
9. 3. 5    Site Visits A fter V acci n ati o n (Visit 4 : D a y 7 5 0 [ M 2 5] f or S u bjects fr o m P are nt Tri al 
D E N 3 1 5 [ M e xic o]/ D a y 4 8 0 [ M 1 6] f or S u bjects fr o m P ar e nt Tri al D E N 3 0 4 [ U nite d 
St ates],  a n d Visit 5 : D a y 9 0 0 [ M 3 0] f or S u bjects fr o m P are nt Tri al D E N 3 1 5 
[ M e xic o]/ D a y 6 3 0 [ M 2 1] f or S u bjects fr o m P are nt Tri al D E N 3 0 4 [ U nite d St ates] ) 
A site visit will be perf or me d a fter t he a d mi nistrati o n of t he T D V b o oster or place b o at Visit 4 
( Da y 7 5 0 [ M 2 5] f or s u bj ects fr o m pare nt trial D E N 3 1 5 [ Me xic o]/ Da y 4 8 0 [ M 1 6] f or s u bjects 
fr o m pare nt trial D E N 3 0 4 [ U nite d States]) . T his visit s h o ul d occ ur at least 2 9 da ys after T D V 
b o oste r or place b o a d mi nistrati o n. A site visit will als o be perf or me d at Visit 5  ( Da y 9 0 0 [ M 3 0] 
f or s u bj ects fr o m pare nt trial D E N 3 1 5 [ Me xic o]/ Da y 6 3 0 [ M 2 1] f or s u bj ects fr o m pare nt trial 
D E N 3 0 4 [ U nite d States]) . 
T he f oll o wi n g pr oce d ures will be perf or me d at Visit 4  ( Da y 7 5 0 [ M 2 5] f or s u bj ects fr o m pare nt 
trial D E N 3 1 5 [ Me xic o]/ Da y 4 8 0 [ M 1 6] f or s u bj ects fr o m pare nt trial D E N 3 0 4 [ U nite d States]) : 
9. 3. 5  
8.    T he site sh o ul d sc he d ule t he ne xt site visit or ot her trial acti vit y wit h t he s u bj ect or t he 
s u bj ect’s L A R ( Visit 5): Da y 9 0 0 [ M 3 0] f or s u bj ects fr o m pare nt trial D E N-3 1 5 
[ Me xic o]/ Da y 6 3 0 [ M 2 1] f or s u bj ects fr o m pare nt trial D E N-3 0 4 [ U nite d States] . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 3 9  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
T he s u bj ect or t he s u bj ect’s L A R will recei ve a writte n re mi n der of t he ne xt pla n ne d trial a cti vit y 
( Visit 5: Da y 9 0 0 [ M 3 0] f or s u bj ects fr o m pare nt trial D E N 3 1 5 [ Me xic o]/ Da y 6 3 0 [ M 2 1]  f or 
s u bj ects fr o m pare nt trial D E N 3 0 4 [ U nite d States] ). T he s u bj ect or t he s u bj ect’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 uesti o ns a n d t o c o ntact t he site i m me diatel y ( or as 
s o o n as t he s u bj ect is me dicall y sta ble) if t he s u bj ect 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 . 
T he f oll o wi n g pr oce d ures will be perf or me d at Visit 5 ( Da y 9 0 0 [ M 3 0] f or s u bj ects fr o m pare nt 
trial D E N 3 1 5 [ Me xic o]/ Da y 6 3 0 [ M 2 1] f or s u bj ects fr o m pare nt trial D E N 3 0 4 [ U nite d States]) : 
9. 3. 6  
A n a d diti o nal  sec o n d rete nti o n p h o ne call will be ma de t o s u bj ects fr o m pare nt trial D E N-3 1 5 
( Me xic o) bet wee n Visits 2 a n d 3 o n Da y 6 3 0 ( M 2 1) D ay 5 4 0 ( M 1 8)  t o mai ntai n c o ntact wit h t he 
s u bj ect/t he s u bj ect’s L A R bet wee n site visits, a n d t o re mi n d t he s u bj ect/t he s u bj ect’s L A R of t he 
b o oster eli gi bilit y criteria a n d t he u pc o mi n g site visit. Fe mal e s u bj ects of c hil d beari n g a ge will 
als o be re mi n de d of pre g na nc y a v oi da nce g ui da nce a n d acc e pta ble met h o ds of c o ntrace pti o n 
d uri n g t his ca ll. 
T ele p h o ne c o ntacts will als o b e ma de f or t h ose 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 n g w he n a site visit ca n n ot be carrie d o ut d ue t o e xce pti o n al circ u mst a nces s uc h as t he 
C O VI D -1 9 pa n de mic.  
9. 3. 7  
F or s u bj ects w h o fail t o meet t he criteria f or ‘ b o oster eli gi bilit y’ at Visit 3 B ( Da y 7 2 0 [ M 2 4] ) f or 
s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt 
trial D E N 3 0 4 ( U nite d States) , t he fi nal (e n d of trial) visit will be perf or me d at Visit 3B/ Visit 3 
(Da y 7 2 0 [ M 2 4] / Da y 4 5 0 [ M 1 5]), res pecti vel y. F or t h ose s u bj ects w h o meet t he criteria f or 
‘ b o oster eli gi bilit y’ a n d are ra n d o mize d t o Gr o u p 1 or Gr o u p 2, t he fi nal (e n d of trial) visit will 
be perf or me d at Visit 5  (Da y 9 0 0 [ M 3 0]  f or s u bj ects fr o m pare nt trial D E N 3 1 5 [ Me xic o]/ Da y 
6 3 0 [ M 2 1] f or s u bj ects fr o m pare nt trial D E N 3 0 4 [ U nite d States]) . 
1 0. 0  
N ote t hat t he ti mi n g of Visit 1, Visit 2, a n d Visit 3 A/ 3  will b e t he sa me f or all s u bj ects 
( Da y 1  [ M 0], Da y 3 6 0 [ M 1 2], a n d Da y 4 5 0 [ M 1 5], res pecti vel y), b ut f or o perati o nal reas o ns, 
a d mi nistrati o n of t he b o oster d ose will be dela ye d u ntil Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects 
fr o m pare nt trial D E N-3 1 5 ( Me xic o). I n s u bj ects w h o recei ve t he T D V b o oster or place b o, Visit 
4 a n d Visit 5 will occ ur at 1 m o nt h a n d 6 m o nt hs p ost b o oster, res pecti vel y: Da y 7 5 0 ( M 2 5) a n d 
Da y 9 0 0  ( M 3 0) f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Da y 4 8 0 ( M 1 6) a n d Da y 6 3 0 
( M 2 1) f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States). F or all s u bj ects, Visit 1, Visit 2, 
a n d Visit 3 A/ 3  c orres p o n d t o 2 1 m o nt hs, 3 3 m o nt hs, a n d 3 6 m o nt hs after t he fi rst vacci nati o n i n 
t he pri mar y vacci nati o n series, res pecti vel y. F or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o), 
Visit 3 B, Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 4 5 m o nt hs, 4 6 m o nt hs a n d 5 1 m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series, r es pecti vel y. F or s u bj ects fr o m pare nt 
trial D E N-3 0 4 ( U nite d States), Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 3 7 m o nt hs a n d 4 2 
m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series, res pecti vel y.  
N ote, f or all s u bject s Visit 1 ( D ay 1 [ M 0]) a n d Visit 2 ( D ay 3 6 0 [ M 1 2]) c orres p o n d t o 
2 1  m o nt hs a n d 3 3 m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series i n t he 
p are nt tri al. F or s u bjects fr o m p are nt tri al D E N -3 1 5 ( Me xic o), Visit 3 ( D ay 1 2 6 0 [ M 4 2]), Visit 
4 ( D ay 1 2 9 0 [ M 4 3]), a n d Visit 5 ( D ay 1 4 4 0 [ M 4 8 ]) i n t his tri al c orres p o n d t o 6 3 m o nt hs, 6 4 
m o nt hs, a n d 6 9  m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series, 
res pectively. F or s u bjects fr o m p are nt tri al D E N-3 0 4 ( U nite d St ates), Visit 3 ( D ay 4 5 0 [ M 1 5]), 
Visit 4 ( D ay 4 8 0 [ M 1 6]), a n d Visit 5 ( D ay 6 3 0 [ M 2 1]) i n t his tri al c orres p o n d t o 3 6 m o nt hs, 
3 7  m o nt hs, a n d 4 2 m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series i n t he 
p are nt tri al, res pectively.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 4 0  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
1 0. 1. 2  
F o ot n ote: T a ble 1 0. a  S olicite d L oc al (I njecti o n Site) Re a cti o ns a n d S yste mic A Es  
(a)   Fe ver is defi ne d as b o d y t e m perat 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 [1 7 1 8 ]. 
1 0. 1. 2  
F o ot n ote: T a ble 1 0. b  S olicite d s afet y p ar a meters  
( b)   Fe ver is defi ne d as b o dy te m per at 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 [ 1 7 1 8 ]. 
1 0. 4. 1  
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 trial a n d will b e s u m marize d u p t o Visit 3B ( Da y 7 2 0 [ M 2 4]   (pre -vacci nati o n)  
f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]  pre -vacci nati o n) f or 
s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States)  a n d se paratel y t hereafter ( p ost -vacci nati o n) 
b y trial gr o u p u p t o Visit 5  (D a y 9 0 0 [ M 3 0]  f or su bj ects fr o m pare nt trial D E N -3 1 5 
[ Me xic o]/ Da y 6 3 0 [ M 2 1] f or s u bj ects fr o m pare nt trial D E N-3 0 4 [ U nite d States] ). 
1 0. 4. 2  
T he occ urre nce of selecte 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 bj ects 
f or 7 da ys (s olicite d l ocal [i nj ecti o n site] A Es) 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 t he T D V b o oster or place b o d ose at Visit 3 B  ( Da y 7 2 0 [ M 2 4]) f or s u bj ects 
fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial 
D E N 3 0 4 ( U nite d States),  (i ncl usi ve of 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 A Es” e C R F , as a p plica ble . 
1 0. 4. 3  
M A A Es will be c ollecte d b y cl ose m o nit ori n g of Gr o u ps 1 a n d 2, f oll o wi n g a d mi nistrati o n of t he 
T D V b o oster or place b o fr o m Visit 3 B ( Da y 7 2 0 [ M 2 4] f or s u bj ects fr o m pare nt trial D E N -3 1 5 
[ Me xic o])/fr o m Visit 3 ( Da y 4 5 0 [ M 1 5] f or s u bj ects fr o m pare nt trial D E N-3 0 4 [ U nite d St ates])  
t hr o u g h Visit 5  ( Da y 9 0 0 [ M 3 0] f or s u bj ects fr o m pare nt trial D E N-3 1 5 [ Me xic o]/ Da y 6 3 0 
[ M 2 1] f or s u bj ects fr o m pare nt trial D E N-3 0 4 [ U nite d States] . 
1 0. 4. 4  
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 bj ect is e nr olle d i n t he trial ( Visit 1  
[ 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 ( Visit 3 B [ Da y 
7 5 0 ( M 2 5)]  f or s u bj ects w h o fail t o meet t he criteria f or ‘ b o oster eli gi bilit y’ a n d Visit 5 [ Da y 9 0 0 
( M 3 0)], f or all ot her s u bj ects fr o m pare nt trial D E N 3 1 5 [ Me xic o]/ Visit 3 [ Da y  4 5 0 ( M 1 5)] f or 
s u bj ects w h o fail t o meet t he criteria f or ‘ b o oster eli gi bilit y’ a n d Visit 5 [ Da y 6 3 0 ( M 2 1)], f or all 
ot her s u bj ects fr o m pare nt trial D E N 3 0 4 [ U nite d States] ). 
1 2. 1  
W he n a site visit ca n n ot b e carrie d o ut d ue  t o e xce pti o n al circ u mst a nces s uc h as  t he C O VI D-1 9 
pa n de mic, tele p h o ne c o ntacts 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 s afet y 
re p orti n g. Refer als o t o Secti o n 1 4. 1.  
1 3. 0  
N ote t hat t he ti mi n g of Visit 1, Visit 2, a n d Visit 3 A/ 3  will b e t he sa me f or all s u bj ects 
( Da y 1  [ M 0], Da y 3 6 0 [ M 1 2], a n d Da y 4 5 0 [ M 1 5], res pecti vel y), b ut f or o perati o nal reas o ns, 
a d mi nistrati o n of t he b o oster d ose will be dela ye d u ntil Visit 3 B ( Da y 7 2 0 [ M 2 4]) f or s u bj ects 
fr o m pare nt trial D E N 3 1 5 ( Me xic o). I n s u bj ects w h o recei ve t he T D V b o oster or place b o, Visit 
4 a n d Visit 5 will occ ur at 1 m o nt h a n d 6 m o nt hs p ost b o oster, res pecti vel y: Da y 7 5 0 ( M 2 5) a n d 
Da y 9 0 0 ( M 3 0) f or s u bj ects fr o m pare nt trial D E N
3 1 5 ( Me xic o)/ Da y 4 8 0 ( M 1 6) a n d Da y 6 3 0 
( M 2 1) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States). F or all s u bj ect s, Visit 1, Visit 2, 
a n d Visit 3 A/ 3  c orres p o n d t o 2 1 m o nt hs, 3 3 m o nt hs, a n d 3 6 m o nt hs after t he first vacci nati o n i n 
t he pri mar y vacci nati o n series, res pecti vel y. F or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o), 
Visit 3 B, Visit 4, a n d Visit 5 i n t his trial  c orres p o n d t o 4 5 m o nt hs, 4 6 m o nt hs a n d 5 1 m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series, r es pecti vel y. F or s u bj ects fr o m pare nt 
trial D E N 3 0 4 ( U nite d States), Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 3 7 m o nt hs a n d 
4 2  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series, res pecti vel y . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 4 1  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
N ote, f or all s u bjects Visit 1 ( D ay 1 [ M 0]) a n d Visit 2 ( D ay 3 6 0 [ M 1 2]) c orres p o n d t o 
2 1  m o nt hs a n d 3 3 m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series i n t he 
p are nt tri al. F or s u bjects fr o m p are nt tri al D E N -3 1 5 ( Me xic o), Visit 3 ( D ay 1 2 6 0 [ M 4 2]), Visit 
4 ( D ay 1 2 9 0 [ M 4 3]), a n d Visit 5 ( D ay 1 4 4 0 [ M 4 8 ]) i n t his tri al c orres p o n d t o 6 3 m o nt hs, 6 4 
m o nt hs, a n d 6 9  m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series, 
res pectively. F or s u bjects fr o m p are nt tri al D E N-3 0 4 ( U nite d St ates), Visit 3 ( D ay 4 5 0 [ M 1 5]), 
Visit 4 ( D ay 4 8 0 [ M 1 6]), a n d Visit 5 ( D ay 6 3 0 [ M 2 1]) i n t his tri al c orres p o n d t o 3 6 m o nt hs, 
3 7  m o nt hs, a n d 4 2 m o nt hs after t he first v acci n ati o n i n t he pri m ary v acci n ati o n series i n t he 
p are nt tri al, res pectively.  
1 3. 1  
A statistical a nal ysis pla n ( S A P) will be pre pare d a n d fi naliz e d pri or t o u n bli n di n g of s u bj ect ’s’ 
trial ar m assi g n me nt. T his d oc u me nt will pr o vi de f urt her details re gar di n g t he defi niti o n of 
a nal ysis varia bles a n d a nal ysis met h o d ol o g y t o a d dress all trial o bj ecti ves.  
A b B li n de d data re vie ws will be c o n d ucte d pri or t o t he u n bli n di n g of s u bj ec ts’ trial ar m 
assi g n me nt. T his T hese  re vie ws will assess t he acc urac y a n d c o m plete ness of t he trial data b ase , 
a n d s u bj ect e val ua bilit y. 
1 3. 1. 1  
All Scree ne d: All s u bjects w h o a gree d t o p artici p ate i n t he c urre nt tri al.  
All Scree ne d -B o oster:  All s u bjects w h o a gree d t o p artici p ate i n t he c urre nt tri al a n d w h o were 
scree ne d f or ‘ b o oster eli gi bility’ t o deter mi ne if t hey were  eli gi ble t o g o o n t o be r a n d o mize d t o 
Gr o u p 1 or Gr o u p 2.  
R a n d o mize d Set -B o oster: All s u bjects r a n d o mize d at Visit 3 re g a r dless of w het her t hey 
receive d t he tri al v acci n ati o n i n t he c urre nt tri al. S u bjects i n t his set will be s u m m arize d 
acc or di n g t o r a n d o mize d tre at m e nt.  
1 3. 1. 1  
F ull A n al ysis Set ( F A S):  All s u bj ects w h o recei ve d at least o ne d ose of T a ke da’s T D V i n t he 
pare nt trials a n d f or w h o m t here is at least o ne vali d f oll o w -u p meas ure me nt u p t o Visit 3 B ( Da y 
7 2 0 [ M 2 4] ) f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ u p t o Visit 3  ( Da y 4 5 0 [ M 1 5]) f or 
s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States)  f or i m m u n o ge nicit y assess me nts i n t he 
c urre nt trial.  
F ull A n al ysis Set -B o oster ( F A S -B):  All s u bj ects w h o recei ve d at least o ne d ose of T a ke da’s 
T D V i n t he pare nt trials, t he T D V b o oste r or place b o i n t he c urre nt trial, a n d f or w h o m t her e is at 
least o ne vali d f oll o w-u p meas ure me nt after a d mi nistrati o n of t he T D V b o oster or place b o at 
Visit 3 B ( Da y 7 2 0 [ M 2 4] ) f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 ( Da y 4 5 0 
[ M 1 5]) f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d Stat es)  f or i m m u n o ge nicit y assess me nts 
i n t he c urre nt trial. 
Per Pr ot oc ol Set ( P P S):  All s u bj ects fr o m t he F A S w h o recei ve d t w o d oses of T a ke da’s T D V i n 
t he pare nt trials wit h n o ne w maj or pr ot oc ol vi olati o ns pri or to a d mi nistrati o n of t he b o oster or 
place b o at Visit 3 B ( Da y 7 2 0 [ M 2 4] ) f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o)/ Visit 3 
( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States)  t hat c o ul d p ote nti all y 
c o nf o u n d t he pri mar y e n d p oi nts i n t he c urre nt trial.  
Per Pr ot oc ol Set -B o oster ( P P S -B):  All s u bj ects fr o m t he F A S -B w h o recei ve d t w o d oses of 
T a ke d a’s T D V i n t he pare nt trials wit h n o ne w maj or pr ot oc ol vi olati o ns after a d mi nistrati o n of 
t he T D V b o oster or place b o at Visit 3B ( Da y 7 2 0 [ M 2 4] ) f or s u bj ects fr o m pare nt trial D E N-3 1 5 
( Me xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5]) f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States)  t hat 
c o ul d p ote ntiall y c o nf o u n d t he pri mar y e n d p oi nts i n t he c urr e nt trial.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 4 2  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
T he maj or pr ot oc ol vi olati o n criteri o n will be defi n e d as part of a data re vie w pri or t o a nal ysis. 
T he cate g ories of ne w 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 crit eria, 
( 2) recei vi n g t he wr o n g trial vacci nati o n at Visit 3B ( Da y 7 2 0 [ M 2 4] ) f or s u bj ects fr o m par e nt 
trial D E N 3 1 5 ( M e xic o)/ Visit 3 ( Da y 4 5 0 [ M 1 5] f or s u bjects fr o m pare nt trial D E N 3 0 4 ( U nite d 
States); (s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 o nl y),  
1 3. 1. 3  
F or t he pri mar y a n d sec o n dar y i m m u n o ge nicit y e n d p oi nts (ie, G M Ts of ne utralizi n g a nti b o dies 
a n d ser o p ositi vit y rates f or eac h of t he 4 de n g ue ser ot y pes a n d m ulti ple [ 2, 3 or 4]), descri pti ve 
statistics a n d 9 5 % CIs will be pr o vi de d f or eac h a p plica ble visit ( Visit  1  [ Da y 1  ( M 0)], Visit 2 
[ Da y 3 6 0 ( M 1 2)], Visit 3 A [ Da y 4 5 0 ( M 1 5)],  Visit 3 B [ Da y 7 2 0 ( M 2 4)] , Visit 4  [ Da y 7 5 0 
( M 2 5)], a n d Visit 5 [ Da y 9 0 0 ( M 3 0)] i n t he c urre nt trial f or s u bj ects fr o m pare nt trial D E N-3 1 5 
[ Me xic o]/ Visit 1 [ Da y 1 ( M 0)], Visit 2 [ Da y 3 6 0 ( M 1 2)], Visit 3 [ Da y 4 5 0 ( M 1 5)], 
Visit  4  [ Da y 4 8 0  ( M 1 6)], a n d Visit 5 [ Da y 6 3 0 ( M 2 1)] i n t he c urre nt trial f or s u bj ects fr o m 
pare nt trial D E N -3 0 4 [ U nite d States] , a n d f or Da y 1 2 0 [ M o nt h 4] a n d Da y 2 7 0 [ M o nt h 9] i n b ot h  
t he pare nt trials [ w hic h c orres p o n ds t o 4  m o nt hs a n d 9 m o nt hs after t he first vacci nati o n i n t he 
pri mar y vacci nati o n series i n t he pare nt trials, res pecti vel y]) . 
1 3. 1. 4  
U ns olicite d A Es...  
A Es lea di n g t o trial or vacci ne wit h dra wal will be s u m mariz e d u p t o Visit 3 B (Da y 7 2 0 [ M 2 4] 
 
pre -vacci nati o n) a n d t hereafter ( p ost -vacci nati o n) b y trial gr o u p u p t o Visit 5  ( Da y 9 0 0 [ M 3 0]) 
f or s u bj ects fr o m pare nt trial D E N 3 1 5 ( Me xic o)/ u p t o Visit 3 
( Da y 4 5 0  [ M 1 5]  pre vacc i nati o n) a n d t hereafter ( p ost vacci nati o n) b y trial gr o u p u p t o Visit 5 
( Da y 6 3 0 [ M 2 1]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 ( U nite d States) . 
U ns olicite d A Es will be ta b ulate d at eac h of t he f oll o wi n g le vels: o verall s u m mar y (s u bj ects wit h 
at least 1 A E) , a n d b y S O C a n d P T. I n a d diti o n, 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 fr e q ue nc y greater 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 Statistical A nal ysis Pla n S A P ); b y S O C a n d P T; b y S O C, P T, an 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 vacci ne ( T D V b o oster or place b o).  
1 3. 1. 4  
M A A Es  
M A A Es will be c ollecte d f or s u bj ects ra n d o mize d t o Gr o u p 1 a n d Gr o u p 2 a n d will be prese nte d 
b y trial gr o u p fr o m Visit 3 B  (Da y 7 2 0 [ M 2 4] ) t hr o u g h Visit 5 (Da y 9 0 0 [ M 3 0] ) f or s u bj ects fr o m 
pare nt trial D E N -3 1 5 ( Me xic o)/fr o m Visit 3 ( Da y 4 5 0 [ M 1 5]) t hr o u g h Visit 5 ( Da y 6 3 0 [ M 2 1]) 
f or s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nite d States) . M A 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 S O C a n d P T f or eac h trial gr o u p . 
1 3. 1. 4  
S A Es  
S A Es will be c ollecte d t hr o u g h o ut t he tria l. 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 u p t o Visit 3B ( Da y 7 2 0 [ M 2 4] ) ( pre-v acci n ati o n) a n d t hereafter 
( p ost-vacci nati o n) b y trial gr o u p u p t o Visit 5  (Da y 9 0 0 [ M 3 0] ) f or s u bj ects fr o m pare nt tri al 
D E N 3 1 5 ( Me xic o)/ u p t o Visit 3 ( D a y 4 5 0 [ M 1 5]  pre vacci nati o n) a n d t hereafter ( p ost
vacci nati o n) b y trial gr o u p u p t o Visit 5 ( Da y 6 3 0 [ M 2 1]) f or s u bj ects fr o m pare nt trial D E N 3 0 4 
( U nite d States). 
1 3. 2  
N o i nteri m a nal yses are pla n ne d.  
D ue t o si g nific a nt del ays ( of > 2 ye ars) t o b o oster a d mi nistr ati o n f or s u bjects fr o m p are nt tri al 
D E N -3 1 5 ( Me xic o), a n i nteri m a n alysis  (I A) of t he s afety a n d i m m u n o ge nicity d at a c ollecte d 
at tri al sites i n t he U nite d St ates is pl a n ne d w he n all s u bjects fr o m p are nt tri al D E N -3 0 4 
( U nite d St ates) h ave c o m plete d t heir l ast tri al visit ( Visit 5 [ D ay 6 3 0 ( M 2 1)]). T his I A will be 
perf or m e d i n a n u n bli n de d m a n ner a n d w ill i ncl u de t he ne cess ary ste ps t o e ns ure t h at n o 
d at a b ase m o dific ati o ns are m a de after u n bli n di n g f or s u bjects at tri al sites i n t he U nite d 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 4 3  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
St ates. U n bli n di n g of s u bjects fr o m p are nt tri al D E N -3 1 5 ( Me xic o) will occ ur after  all s u bjects 
at tri al sites i n M e xic o h ave c o m plete d t heir l ast tri al visit ( Visit 5 [ D ay 1 4 4 0 ( M 4 8 )]) a n d t he 
tri al d at a b ase h as bee n  l oc ke d. N o m o dific ati o ns t o t he tri al  are pl a n ne d  b ase d o n t he res ults 
of t his  I A. A n i nteri m C S R of d at a fr o m p are nt tri al D E N-3 0 4 ( U nite d St ates) will n ot be 
pre p are d ; all tri al res ults will be re p orte d i n t he fi n al C S R. M ore det ails re g ar di n g t he I A will 
be  pr ovi de d i n t he S A P.  
1 4. 1  
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 e xce pti o n al circ u mst a nces 
s uc h as t he C O VI D-1 9 pa n de mic, alter nati ve m o nit ori n g a p pr oac hes s uc h as re m ote s o urc e data 
verificati o n or tele p h o ne c o nta ct ma y be use d t o e ns ure data q ualit y a n d i nte grit y a n d t o mai ntai n 
s u bj ect safet y. 
1 5 . 4. 1 
I n or der t o e ns ure t hat i nf or mati o n o n cli nical trials reac hes 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 plica ble la w, r e g ulati o n a n d g ui da 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 bj ects 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 / or E u dra C T, acc or di n g t o l ocal re q uire me nts, bef ore trial 
i nitiati o n. 
1 5. 4. 2  
I n li ne wit h E C Re g ulati o n N° 1 9 0 1/ 2 0 0 6 [1 8 1 9 ], t he s p o ns or will s u b mit a s u m mar y of t he 
res ults of a pe diatric trial wit hi n si x6  m o nt hs of c o m pleti o n a n d irres pecti ve of w het her it is part 
of a P e diatric I n vesti gati o nal Pla n (c o m plete d or n ot yet c o m plete d) or n ot, or w het her it is 
i nte n de d f or s u b missi o n later o n as part of a variati o n, e xte nsi o n or ne w sta n d-al o ne mar keti n g 
a ut h orizati o n a p plicati o n or n ot.  
1 6. 0  
5.  
W orl d Healt h Or ga nizati o n.  D e n g ue a n d se vere de n g ue. Fact S heet. 2 0 2 0 2 0 2 2 . 
( A vaila ble at: htt p:// w w w. w h o.i nt/ me diace ntre/facts heets/fs 1 1 7/e n/) (accesse d 2 2  
Fe br uar y 2 0 2 1 2 9  J u ly 2 0 2 2 ). 
7.  
W orl d Healt h Or ga nizati o n. D e n g ue he 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 , 2n d  E diti o n.  Ge ne va  1 9 9 7.  2 n d E diti o n . ( A vaila ble at: 
htt p:// w w w. w h o.i nt/csr/res o ur ces/ p u blicati o ns/ de n g ue/ De n g ue p u blicati o n/e n/ htt ps:// a p p
s. w h o.i nt/iris/ h a n dle/ 1 0 6 6 5/ 4 1 9 8 8) (accesse d 2 2 Fe br uar y 2 0 2 1 2 9  J uly 2 0 2 2 ). 
8.  
W orl d Healt h Or ga nizati o n. D e 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 : ne w e diti o n. 2 0 0 9. ( A vaila ble at: 
htt p:// w w w. w h o.i nt/t dr/ p u blic ati o ns/ d oc u me nts/ de n g ue
dia g n osis. p df htt ps:// a p ps. w h o.i nt/iris/ h a n dle/ 1 0 6 6 5/ 4 4 1 8 8 ) (accesse d 2 2 Fe br uar y 
2 0 2 1 2 9  J uly 2 0 2 2 ). 
1 5.  
Bis wal S, Re y nales H, Saez Ll ore ns X, L o pez P, B orj a T a b ora C, K osalara ksa P, et al. 
Efficac y of a T etra vale nt De n g ue Vacci ne i n Healt h y C hil dre n a n d A d olesce nts. N E n gl 
J Me d. 2 0 1 9; 3 8 1( 2 1): 2 0 0 9 1 9. Bis w al S, B orj a -T a b or a C, M arti nez V ar g as L, 
Vel ás q uez H,  T heres a Aler a M, Sierr a V, et al; TI D E S st u dy gr o u p. Effic acy of a 
tetr av ale nt de n g ue v acci ne i n he alt hy c hil dre n a ge d 4-1 6 ye ars: a r a n d o mise d, 
pl ace b o -c o ntr olle d, p h ase 3 tri al. L a ncet. 2 0 2 0 M a y 2; 3 9 5( 1 0 2 3 4): 1 4 2 3 -3 3.  
1 6.  
P atel S S, R a usc her M, K u del a M, P a n g H. Cli nic al S afety E x perie nce of T A K -0 0 3 
f or De n g ue Fever: a ne w Tetr av ale nt Live Atte n u ate d V acci ne C a n di d ate. Cli n I nfect 
Dis. 2 0 2 2 M a y 2 6:ci ac 4 1 8.  
1 6 1 7 . 
W orl d Healt h Or ga nizati o n. Re d uci n g pai n at t he ti me of va cci nati o n: W H O p ositi o n 
pa p er - Se pte 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.  
1 7 1 8 . 
K o hl K S, Marc y S M, Bl u m M, C o n nell J o nes M, Da ga n R, Ha nse n J, et al. Fe ver after 
i m m u nizati o n: c urre nt c o nce pts a n d i m pr o ve d f ut ure scie ntifi c u n dersta n di n g. Cli n 
I nfect Dis. 2 0 0 4; 3 9( 3): 3 8 9-9 4.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 4 4  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Secti o n  
Descri pti o n of C h a n ge  
1 8 1 9 . E C Re g ulati o n N° 1 9 0 1/ 2 0 0 6 O F T H E E U R O P E A N P A R LI A M E N T A N D O F T H E 
C O U N CI L of 1 2 Dece m ber 2 0 0 6 o n me dici nal pr o d ucts f or pe diatric use a n d a me n di n g 
Re g ulati o n ( E E C) N o 1 7 6 8/ 9 2, Directi ve 2 0 0 1/ 2 0/ E C, Directi ve 2 0 0 1/ 8 3/ E C a n d 
Re g ulati o n ( E C) N o 7 2 6/ 2 0 0 4.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 4 5  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
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  ........................................................................................................................2  
1. 3  
Pr ot oc ol Versi o n 5. 0 S u m mar y of C ha n ges  ...................................................................4  
1. 3. 1  Versi o n Hist or y  ........................................................................................................4  
1. 3. 2  S u m mar y of C ha n ges  ...............................................................................................4  
2. 0  
T RI A L S U M M A R Y  ..........................................................................................................5 0  
2. 1  
Sc he d ule of Trial Pr oce d ures  .......................................................................................6 2  
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  ...........................................................................6 6  
3. 1  
Trial -Relate d Res p o nsi bilities  ......................................................................................6 6  
3. 2  
Pri nci pal I n v esti gat or  ...................................................................................................6 6  
3. 3  
List of A b bre viati o ns  ...................................................................................................6 7  
4. 0  
I N T R O D U C TI O N .............................................................................................................6 9  
4. 1  
Bac k gr o u n d  ..................................................................................................................6 9  
4. 2  
Rati o nale f or t he Pr o p ose d Trial  ..................................................................................7 0  
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  ......................................................................7 2  
5. 1  
O bjecti ves  ....................................................................................................................7 2  
5. 1. 1  Pri mar y O bj ecti ves .................................................................................................7 2  
5. 1. 2  Sec o n dar y O bj ecti ves .............................................................................................7 2  
5. 1. 3  E x pl orat or y O bjecti ves  ..........................................................................................7 3  
5. 2  
E n d p oi nts  .....................................................................................................................7 3  
5. 2. 1  Pri mar y E n d p oi nts  .................................................................................................7 3  
5. 2. 2  Sec o n dar y E n d p oi nts  .............................................................................................7 4  
5. 2. 3  E x pl orat or y E n d p oi nts  ...........................................................................................7 5  
6. 0  
T RI A L D E SI G N A N D D E S C RI P TI O N  ...........................................................................7 6  
6. 1  
Trial Desi g n  .................................................................................................................7 6  
6. 2  
J ustificati o n f or Trial Desi g n, D ose, a n d E n d p oi nts ....................................................7 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  ..................7 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  .......................8 0  
6. 4. 1  Criteria f or Pre m at ure T er mi nati o n or S us pe nsi o n of t he Trial  .............................8 0  
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 ..........8 0  
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) ...................................................................8 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  ...............8 1  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 4 6  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
7. 1  
I n cl usi o n Criteria .........................................................................................................8 1  
7. 2  
E x cl usi o n Criteria  ........................................................................................................8 1  
7. 3  
B o oster Eli gi bilit y  ........................................................................................................8 2  
7. 4  
Criteria f or D ela y of Trial Vacci ne or Place b o A d mi nistrati o n or Bl o o d Sa m pli n g  ...8 4  
7. 5  
Criteria f or E arl y Ter mi n ati o n of a S u bject’s Trial Partici pati o n  ................................8 4  
7. 6  
Criteria f or Pre m at ure Disc o nti n uati o n of Trial Vacci ne A d mi nistrati o n  ...................8 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 .........................................................8 7  
8. 1  
Trial Vacci ne, Place b o a n d Materials  ..........................................................................8 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  ......................................8 7  
8. 1. 2  St ora ge  ...................................................................................................................8 8  
8. 1. 3  D ose a n d Re gi me n  .................................................................................................8 8  
8. 2  
Trial Vacci ne Assi g n me nt a n d Dis pe nsi n g Pr oce d ures  ...............................................8 8  
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 T D V B o oster or  Place b o  ..8 9  
8. 3  
Ra n d o mizati o n C o de Creati o n a n d St ora ge  .................................................................8 9  
8. 4  
Trial Vacci ne Bli n d Mai nte na nce  ................................................................................8 9  
8. 5  
U n bli n di n g Pr oce d ure  ..................................................................................................9 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, Place b o, a n d 
Ot her Cli ni cal Trial Materials  ......................................................................................9 0  
9. 0  
T RI A L P L A N  ....................................................................................................................9 2  
9. 1  
Trial Pr oce d ures  ...........................................................................................................9 2  
9. 1. 1  I nf or me d C o nse nt a n d Pe diatric Asse nt F or m .......................................................9 2  
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  ........................................9 3  
9. 1. 3  D oc u me ntati o n of Trial E ntra nce a n d Ra n d o mizati o n  ..........................................9 4  
9. 1. 4  P h ysical E x a mi nati o n .............................................................................................9 5  
9. 1. 5  Vital Si g ns  ..............................................................................................................9 5  
9. 1. 6  I m m un o ge nicit y Assess me nts  ................................................................................9 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  .....................................9 6  
9. 1. 8  Safet y Assess me nts  ................................................................................................9 6  
9. 1. 9  C o ntrace pt i o n a n d Pre g n a nc y A v oi da n ce Pr oce d ure .............................................9 6  
9. 1. 1 0  Pre g n a nc y  ...............................................................................................................9 7  
9. 1. 1 1  D oc u me ntati o n of S u bjects W h o Are N ot C o nsi dere d Eli gi ble f or Trial E ntr y 
( Visit 1) or Ra n d o mizati o n ( Visit 3)  ......................................................................9 7  
9. 2  
M o nit ori n g S u bject C o m plia nce  ..................................................................................9 8  
9. 3  
Sc he d ule of O bser vati o ns a n d Pr oce d ures  ...................................................................9 8  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 4 7  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
9. 3. 1  Site Visits Pri or t o T D V B o oster or Place b o A d mi nistrati o n 
( Visit 1  a n d Visit  2) ................................................................................................9 8  
9. 3. 2  Pre -Vacci nati o n Pr oce d ures ( Visit 3)  ....................................................................9 9  
9. 3. 3  Vacci n ati o n Pr oce d ures ( Visit 3)  .........................................................................1 0 0  
9. 3. 4  P ost -Vacci nati o n Pr oce d ures ( Visit 3)  .................................................................1 0 0  
9. 3. 5  Site Visits After Vacci n ati o n ( Visit 4 a n d Visit 5)  ..............................................1 0 2  
9. 3. 6  P h o ne C o ntact –  Re mi n der Call ( Da y 1 8 0 [ M 6])  ................................................1 0 3  
9. 3. 7  Fi nal ( E n d of Trial) Visit  .....................................................................................1 0 3  
9. 3. 8  P ost -Trial Care  .....................................................................................................1 0 4  
9. 4  
Bi ol o gic al Sa m ple Rete nti o n a n d Destr ucti o n  ...........................................................1 0 4  
1 0. 0  
A D V E R S E E V E N T S  .......................................................................................................1 0 5  
1 0. 1  
Defi niti o ns ..................................................................................................................1 0 5  
1 0. 1. 1  A d verse E v e nts  ....................................................................................................1 0 5  
1 0. 1. 2  S olicite d A d verse E ve nts  .....................................................................................1 0 5  
1 0. 1. 3  A d verse E v e nts of S peci al I nt erest  ......................................................................1 0 7  
1 0. 1. 4  Me dicall y -Atte n de d A d verse E ve nts  ...................................................................1 0 7  
1 0. 1. 5  Seri o us A d verse E v e nts ( S A Es) ...........................................................................1 0 7  
1 0. 2  
Ca usalit y of A Es  ........................................................................................................1 0 8  
1 0. 2. 1  Relati o ns hi p t o Trial Pr oce d ures  ..........................................................................1 0 8  
1 0. 2. 2  O utc o me of A d v erse E v e nts  ................................................................................1 0 8  
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  ....................................................1 0 8  
1 0. 4  
Pr oce d ures  ..................................................................................................................1 0 9  
1 0. 4. 1  C ollecti o n a n d Re p orti n g of A Es  .........................................................................1 0 9  
1 0. 4. 2  C ollecti o n a n d Re p orti n g of S olicite d A Es  ..........................................................1 1 0  
1 0. 4. 3  C ollecti o n a n d Re p orti n g of M A A Es  ..................................................................1 1 1  
1 0. 4. 4  C ollecti o n a n d Re p orti n g of S A Es  .......................................................................1 1 1  
1 0. 5  
F oll o w -U p Pr oce d ures  ...............................................................................................1 1 1  
1 0. 5. 1  A d verse E v e nts  ....................................................................................................1 1 1  
1 0. 5. 2  Seri o us A d verse E v e nts  .......................................................................................1 1 2  
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  .............................1 1 2  
1 0. 5. 4  P ost -Trial E ve nts  ..................................................................................................1 1 2  
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 3  
1 1. 1  
Trial -S pecific C o m mittees  .........................................................................................1 1 3  
1 1. 1. 1  Data M o nit ori n g C o m mittee  ................................................................................1 1 3  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 4 8  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
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  ...........................................................1 1 4  
1 2. 1  
C R Fs ( Electr o nic)  ......................................................................................................1 1 4  
1 2. 2  
Rec or d Rete nti o n  .......................................................................................................1 1 4  
1 3. 0  
S T A TI S TI C A L M E T H O D S  ............................................................................................1 1 6  
1 3. 1  
Statistical a n d A nal ytical Pla ns  ..................................................................................1 1 6  
1 3. 1. 1  A nal ysis Sets  ........................................................................................................1 1 6  
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  ..........................1 1 7  
1 3. 1. 3  I m m u n o ge nicit y A n al ysis ....................................................................................1 1 7  
1 3. 1. 4  Safet y A nal ysis  ....................................................................................................1 1 8  
1 3. 2  
I nteri m A nal ysis a n d Criteria f or Earl y T er mi nati o n .................................................1 1 9  
1 3. 3  
Deter mi nati o n of Sa m ple Size  ...................................................................................1 1 9  
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 2 0  
1 4. 1  
Trial -Site M o nit ori n g Visits  .......................................................................................1 2 0  
1 4. 2  
Pr ot oc ol De viati o ns  ....................................................................................................1 2 0  
1 4. 3  
Q ualit 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  ................................1 2 0  
1 4. 4  
Trial Ris k Ma na ge me nt ..............................................................................................1 2 1  
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  ...........................................................................1 2 2  
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 om mittee A p pr o val  ..........1 2 2  
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  .............................................................................................................1 2 3  
1 5. 3  
S u bject C o nfi de ntialit y  ..............................................................................................1 2 4  
1 5. 4  
Cli nical Trial Re gistrati o n, P u blicati o n a n d Discl os ure P olic y  .................................1 2 4  
1 5. 4. 1  Cli nical Trial Re gistrati o n ....................................................................................1 2 4  
1 5. 4. 2  Cli nical Trial Res ults Discl os ure  .........................................................................1 2 5  
1 5. 4. 3  P u blicati o n of Trial Res ults  .................................................................................1 2 5  
1 5. 5  
I ns ura nce a n d C o m pe nsati o n f or I nj ur y .....................................................................1 2 5  
1 6. 0  
R E F E R E N C E S  ................................................................................................................1 2 6  
 
LI S T O F I N -T E X T T A B L E S  
Ta ble  8.a  
S p o ns or -S u p plie d Vacci nes a n d Place b o  ...............................................................8 8  
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 Es  .............................1 0 6  
Ta ble  1 0. b  
S olicite d Safet y Para met ers  .................................................................................1 0 6  
 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 4 9  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
LI S T O F I N -T E X T F I G U R E S 
Fi g ure  6. a  
Sc he matic of Trial D esi g n  .....................................................................................7 8  
 
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  ......................................................................1 2 8  
A p pe n di x B  
I n v esti gat or C o nse nt t o Use of Perso nal I nf or mati o n  ..........................................1 3 0  
 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 5 0  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
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(s):  
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:  
T a ke da’s 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, F oll o w -U p Trial  t o E val uate L o n g-T er m Safet y a n d A nti b o d y P ersiste nce, a n d t he 
I m pact of a B o oster D ose of a T etra vale nt De n g ue Vacci ne Ca n di date i n Healt h y A d olesc e nts a n d A d ults i n 
Areas N o n -E n de mic f or De n g ue  
I N D N o.: 0 1 4 2 9 2  
E u dr a C T N o.: N ot a p plica ble  
Tri al I de ntifier:  D E N -3 0 3  
P h ase:  3  
Bli n di n g Sc he m a:  O pe n u p t o Visit 3 a n d 
d o u ble -bli n d t hereafter u ntil t he e n d of t he trial  
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 a n d R ati o n ale:  
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 g ue vir us ser ot y pe -1, -2, -3, a n d -4 ( D E N V -1, D E N V -2, D E N V -3, a nd D E N V -4 ). 
T hese de n g ue vir uses are tra ns mitte d fr o m h u ma n t o h u ma n b y m os q uit oes ( pri maril y Ae d es ae gy pti ). T he 
4  de n g ue vir uses 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 P acific Isla n ds, a n d parts 
of Africa. T here are a n esti mat e 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 Healt 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 pitalizati o n wit h a n esti mat e d a n n ual 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 at ris k of de n g ue i nfe cti 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 n ifestati 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 uc o pe nia, a n d occ urri n g 
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 u e 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 it 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 a n d ma y l ea d t o a n i ncrease d 
ris k of se vere disease ( D H F/ D S S) u p o n i nfecti o n wit h o ne of t he ot her 3 de n g ue ser ot y pes.  
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 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 D E N V i nfecti o n is n ot a vaila ble. 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 pr otecti o n are of li mite d efficac y, c o m ple x t o i m pl e 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 uce t he m or bi dit y a n d m ortalit y ass ociate d wit h de n g ue disease. Va cci ne de vel o p me nt 
has f oc use d o n tetra vale nt vac ci nes t hat pr o vi de pr otecti o n a gai nst all 4 de n g ue se r 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 ar eas. 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 vale nt de n g ue vacci ne [ C Y D-T D V]) was a p pr o ve d i n s o me c o u ntries i n 
Asia a n d Lati n A merica i n 2 0 1 5, i n E ur o pe i n 2 0 1 8, a n d i n t he U nite d States i n 2 0 1 9. I nitial fi n di n gs s h o we d t hat 
vacci ne efficac y was differe nt bet 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 . F urt her a nal yses 
s h o we 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 if t he y were i nfecte d 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 ntries 
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 preferr e 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 va cci nate d. He nce, t here 
is a c o nti n ue d u n met p u blic he alt h nee d f or safer a n d m ore efficaci o us de n g ue vacci nes.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 5 1  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
T a ke d a’s 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 a ke d a’s T D V  c o nsists of 1 m olec ularl y c haracterize d, atte n uate d de n g ue ser ot y pe 2 vir us strai n a n d 
3  rec o m bi na nt d e 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 de n g ue s er ot y pes 1, 3, a n d 4 . 
T he de n g ue ser ot y pe 2 strai n ( T D V -2) is base d u p o n t he atte n uate d la b orat or y -deri ve d vir us 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 h aila n d  a n d ge nerate d b y 5 3 s erial 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 D V -2 wit h t he pr M a n d E ge nes fr o m 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, res pecti vel y. T h us , T a k e d a’s T D V  is c o m prise d of 4 de n g ue vir us strains: T D V -2 ( a m olec ularl y 
c haracterize d  atte n uate d strai n ), 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).  
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 nicit y, sa fet y 
a n d i m m u n o ge nicit y pr ofiles f or T a ke d a’s 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 meri ca. C o m plete d p hase 2 cli nical trials ha ve e na ble d 
t he selecti o n of a fi nal T D V  d ose (i n a l y o p hilize d f or m ulati o n) a n d a 2-d ose vacci nati o n s eries 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 cli nical de vel o p me nt 
pr o gra m. Res ults fr o m t he pi v otal D E N -3 0 1 efficac y trial s h o we d t hat t he pri mar y e n d p oi nt was met, 
de m o nstrati n g t hat T D V was efficaci o us i n pre ve nti n g de n g ue fe ver i n c hil dre n a n d a d olesce nts li vi n g i n 
de n g ue -e n de mic c o u ntries. T D V has bee n gi ve n t o > 2 0 ,0 0 0 cli nical trial s u bj ects. All a vaila ble data als o s h o we d 
t hat T D V was well t olerate d wit h n o si g nifica nt safet y c o nc er ns t o date. 
T he c urre nt versi o n of t he I n vesti gat or’s Br oc h ure c o ntai ns 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 pre-cli nical a n d cli nical trials.  
R ati o n ale f or t he Pr o p ose d Tri al:  
T his p hase  3 trial will ca pt ure l o n g -ter m a nti b o d y persiste nc e a n d safet y data in healt h y s u bj ects i n areas 
n o n -e n de mic f or de n g ue w h o ha ve pre vi o usl y recei ve d a pri mar y T D V  vacci nati o n. I t will t he n g o o n t o assess 
t he i m m u n o ge nicit y a n d safet y of a T D V  b o oster d os e i n t his p o p ulati o n. 
S u bj ects pre vi o usl y e nr olle d i n t w o pare nt trials ( D E N -3 0 4 a n d D E N -3 1 5) will i nitiall y be i n vite d t o partici pate 
i n t he D E N-3 0 3 f oll o w -u p trial fr o m 2 1 m o nt hs after t he first vacci nati o n i n t he pri mar y va cci nati o n series i n t he 
pare nt  trials. A nti b o d y persist e nce will be assesse d i n all s u bj ects f or u p t o 6 3  m o nt hs after t he first vacci nati o n 
i n t he pri mar y vacci nati o n seri es f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o) a n d f or u p t o 3 6  m o nt hs after 
t he first vacci nati o n i n t he pri mar y vacci nati o n series f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States). T he 
i m pact of a T D V b o oster vers us place b o o n t he i m m u ne res p o nse will be assesse d at 1 m o nt h a n d 6 m o nt hs after 
b o oster a d mi nistrati o n i n all eli gi ble s u bj ects ra n d o mize d t o re cei ve t he T D V b o oster or place b o (i n a 1: 1 rati o). 
Safet y assess me nts will c o nti n ue f or t he d urati o n of t he trial ( u p t o 6 m o nt hs p ost b o oster a d mi nistrati o n) . 
T he safet y a n d i m m u n o ge nicit y data c ollecte d i n t his trial will be of i m p orta nce n ot o nl y t o i n d i vi d uals tra velli n g 
t o e n de mic re gi o ns b ut als o f or t he si g nifica nt n u m ber of resi de nts wit h n o pri or hist or y of de n g ue i nfecti o n w h o 
li ve i n e n de mic a n d se mi-e n de mic areas. T he i ntr o d ucti o n of a T D V  b o oster i n a n o n -e n de mic setti n g will be gi n 
t he assess me nt of  w het her a b o oster is li kel y t o be of be nefit i n t his p o p ulati o n.  
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 n isati o n of 
T ec h nical Re q uire me nts f or P har mace uticals f or H u ma n Us e  (I C H), 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.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 5 2  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Tri al Desi g n:  
T his is a p hase 3 f oll o w -u p tri al t hat will e val uate t he l o n g -t er m a nti b o d y persiste nce a n d safet y of T a ke da’s 
T D V i n healt h y a d olesce nts a n d a d ults i n areas n o n -e n de mi c f or de n g ue, i n a d diti o n t o assessi n g t he i m pact of a 
b o oster d ose i n t his p o p ulati o n. S u bj ects w h o pre vi o usl y recei ve d T D V i n t w o pare nt trials, D E N -3 0 4 a n d 
D E N -3 1 5, will be i n vite d t o partici pate i n t his f oll o w -u p trial. D E N -3 0 3 will i ncl u de u p t o 6 0 0 healt h y s u bj ects 
a ge d ≥1 3 t o ≤6 3 years at trial e ntr y. T o e na ble t he assess me nt of a b o oster d ose, t he trial will be d o u ble -bli n de d, 
ra n d o mize d, a n d place b o-c o ntr olle d fr o m Visit 3 o n war ds.  
A nti b o d y persiste nce a n d safet y will be assesse d fr o m Visit 1 t hr o u g h Visit 3 f or u p t o 6 3  m o nt hs after t he first 
vacci nati o n i n t he pri mar y vac ci nati o n series f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o) a n d f or u p t o 
3 6  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series f or s u bj ects fr o m pare nt trial D E N-3 0 4 
( U nite d States). F urt her c haracterizati o n of t he l o n g-ter m h u m oral a n d cell-me diate d i m m u ne res p o nses t o 
T a ke d a’s T D V will be u n derta ke n i n a s u bset of a p pr o xi matel y 5 0 v ol u nteers i de ntifie d at e nr oll me nt 
(cell-me diate d i m m u nit y [ C MI] s u bset: partici pati o n is o n a v ol u ntar y basis fr o m D E N -3 0 4 o nl y) u p t o Visit 5. A 
rete nti o n p h o ne call will be ma d e bet wee n Visits 1 a n d 2 o n Da y 1 8 0 ( M 6) t o mai ntai n c o ntact wit h t he 
s u bj ect/t he s u bj ect’s le gall y ac ce pta ble re prese ntati ve ( L A R) bet wee n site visits a n d t o re mi n d t he s u bj ec t/t he 
s u bj ect’s L A R of a n y u pc o mi n g site visits. At Visit 2 t he sit e will disc uss a n y i nf or mati o n t hat is perti ne nt t o t he 
b o oster p hase of t he trial wit h t he s u bj ect. A sec o n d rete nti o n p h o ne call will be ma de t o s u bj ects fr o m pare nt 
trial D E N-3 1 5 ( Me xic o ) bet wee n Visits 2 a n d 3 o n Da y 5 4 0 ( M 1 8). D ue t o c ha n ges i n t he trial desi g n i n Me xic o 
( pr ot oc ol a me n d me nt 3 , date d 2 2 A u g ust 2 0 2 2 ), all s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o) will be as ke d t o 
re-c o nse nt usi n g a n  u p date d i nf or me d c o nse nt f or m (I C F) o r a n u p date d i nf or me d c o nse nt a n d pe diatric asse nt 
f or m, as a p plica ble, at Visit 3  bef ore a n y f urt her pr ot oc ol -directe d pr oce d ures are perf or me d. A n  oral s u m mar y 
of a n y maj or c ha n ges t hat ha ve bee n ma d e t o t he st u d y will be pr o vi de d t o t he s u bj ect a n d s u bj ect’s L A R w here 
a p plica ble i n a d diti o n t o t he I C F/ Asse nt F or m; t his will be d oc u me nte d i n t he me dical c hart as part of t he re -
c o nse nt pr ocess. Re -c o nse nt d ate s h o ul d als o be d oc u me nte d i n t he electr o nic Case Re p ort F or m (e C R F).  
At Visit 3, f oll o wi n g all sc he d ule d bl o o d dra ws, all s u bj ects will be scree ne d f or ‘ b o oster eli gi bilit y’ t o deter mi ne 
if t he y are eli gi ble t o g o o n t o recei ve t he T D V b o oster i n t he b o oster p hase. A n y s u bj ect w h o fails t o meet t he 
criteria f or ‘ b o oster eli gi bilit y’ will e n d t he trial  at Visit 3 . All eli gi ble s u bj ects will be ra n d o mize d, usi n g a n 
i nteracti ve res p o nse tec h n ol o g y at Visit 3  t o 1 of 2 trial gr o u ps ( Gr o u p 1 a n d Gr o u p 2) i n a 1: 1 rati o stratifie d b y 
pare nt trial a n d ser ostat us at baseli ne i n t he pare nt trials. S u bj ects all o cate d t o Gr o u p 1 will recei ve t he T D V 
b o oster (si n gle d ose) a n d s u bj ects all ocate d t o Gr o u p 2 will recei ve place b o. T he i m pact of t he T D V b o oster o n 
ne utralizi n g a nti b o d y titers a n d ser o p ositi vit y rates will be assesse d at 1 m o nt h a n d 6 m o nt hs after a d mi ni strati o n 
of t he T D V b o oster or place b o. Safet y assess me nts will c o nti n ue f or 6 m o nt hs f oll o wi n g T D V b o oster or place b o 
a d mi nistrati o n f or s u bj ects i n Gr o u ps 1 a n d 2.  
F or s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o), t he d urati o n of t he c urre nt trial will be 4 2  m o nt hs f or s u bj ects 
w h o fail t o meet t he criteria f or ‘ b o oster eli gi bilit y’ at Visit 3 a n d 4 8  m o nt hs f or all ot her s u bj ects.  F or s u bj ects 
fr o m pare nt trial D E N-3 0 4 ( U nite d States), t he d urati o n of t he c urre nt trial will be 1 5 m o nt hs f or s u bj ects w h o 
fail t o meet t he criteria f or ‘ b o oster eli gi bilit y’ at Visit 3 a n d 2 1 m o nt hs f or all ot her s u bj ects. A sc he matic of t he 
trial desi g n is prese nte d bel o w i n Fi g ure 1. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 5 3  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
 
F or all s u bjects, Visit 1 a n d Visit 2 c orres p o n d t o 2 1 m o nt hs a n d 3 3 m o nt hs after t he first va cci n ati o n i n t he pri mar y 
vacci n ati o n series  i n t he pare nt trial. F or s u bjects fr o m pare nt trial D E N-3 1 5 ( Me xic o), Visit 3, Visit 4, a n d Visit 5 i n t his trial 
c orres p o n d t o 6 3 m o nt hs, 6 4 m o nt hs, a n d 6 9 m o nt hs after t he first vacci n ati o n i n t h e pri mar y vacci n ati o n series, res pecti vel y. 
F or s u bjects fr o m pare nt trial D E N-3 0 4 ( U nite d States), Visit 3, Visit 4, a n d Visit 5 i n t his trial c orres p o n d t o 3 6 m o nt hs, 
3 7  m o nt hs , a n d 4 2 m o nt hs after t he first vacci n ati o n i n t h e pri mar y vacci n ati o n series, res pecti vel y. 
*  D ue t o c ha n ges i n t he trial desi g n i n Me xic o, ( P r ot oc ol A me n d me nt 3, date d 2 2 A u g ust  2 0 2 2), all s u bjects fr o m pare nt trial 
D E N -3 1 5 ( Me xic o) will be as ke d t o re -c o nse nt usi n g a n u p date d i nf or me d c o nse nt f or m (I C F) or a n u p date d i nf or me d 
c o nse nt a n d pe diatric asse nt f or m , as a p plica ble, at Visit 3 bef ore a n y f urt h er pr ot oc ol -directe d pr oce d ures are perf or me d. 
A n  oral s u m mar y of a n y maj or c ha n ges  t h at ha ve bee n ma de t o t h e st u d y will be pr o vi d e d t o t he s u bject a n d s u bject’s L A R 
w here a p plica ble i n a d diti o n t o t he I C F/ Asse nt F or m; t his will be d oc u me nte d i n t he me dical c hart as part of t h e re -c o nse nt 
pr ocess. Re -c o nse nt date s h o ul d als o be d oc u me nt e d i n t h e e C R F. 
I m m u n o ge nicit y E v al u ati o n:  
•  
Ne utralizi n g a nti b o dies ( b y mi cr o ne utralizati o n test 5 0 % [ M N T 5 0]) will be meas ure d usi n g bl o o d sa m ples 
c ollecte d fr o m all s u bj ects at Visit 1, Visit 2, a n d Visit 3, a n d als o at Visit 4 a n d Visit 5 f or s u bj ects w h o  are 
ra n d o mize d t o Gr o u ps 1 a n d 2.  
•  
At Visit 3, a lar ger v ol u me of bl o o d will be c ollecte d fr o m all s u bj ects t o assess e x pl orat or y mar kers of t he 
l o n g-ter m h u m oral i m m u ne res p o nse t o T a ke da’s T D V. 
•  
A d diti o nal bl o o d sa m ples will be c ollecte d fr o m s u bj ects i n t he C MI s u bset t o all o w f urt her c haracterizati o n 
of t he l o n g -ter m h u m oral a n d cell-me diate d i m m u ne res p o ns e t o T a ke da’s T D V at Visit 1, Visit 2, a n d 
Visit  3, a n d i n s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 at Visit 4 a n d Visit 5 –  a p plica ble t o s u bj ects fr o m 
pare nt trial D E N -3 0 4 ( U nite d States o nl y).  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 5 4  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
S afet y E v al u ati o n:  
•  Diar y car ds will be distri b ute d t o Gr o u ps 1 a n d 2 at Visit 3  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 ( da y of va cci nati o n + 6 da ys) f oll o wi n g 
a d mi nistrati o n of  t he T D V b o oster or place b o. T hese i ncl u d e: 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 ( da y of vacci nati o n + 1 3 da ys) f oll o wi n g 
a d mi nistrati o n of t he T D V b o oster or place b o . T hese i ncl u d e: fe ver, hea dac he, ast he nia, malaise, a n d 
m yal gia.  
•  
U ns olicite d A Es will be c ollecte d b y i nter vie w a n d rec or de d f or 2 8 da ys ( da y of vacci nati o n + 2 7 da ys) 
f oll o wi n g a d mi nistrati o n of t he T D V b o oster or place b o. 
•  
All seri o us a d verse e ve nts ( S A Es) a n d a n y A Es lea di n g t o s u bj ect disc o nti n uati o n a n d wit h dra wal will be 
c ollecte d f or t he trial d urati o n f or all s u bj ects.  
•  
Me dicall y atte n de d A Es ( M A A Es) will be c ollecte d, f or Gr o u ps 1 a n d 2, f oll o wi n g a d mi nistrati o n of t he 
T D V b o oster or place b o fr om  Visit 3 t hr o u g h Visit 5. M A A Es are defi ne d as A Es lea di n g t o a n u nsc he d ule d 
visit t o or b y a healt hcare pr ofessi o nal i ncl u di n g visits t o a n e mer ge nc y de part me nt, b ut n ot f ulfilli n g 
seri o us ness criteria. 
•  
F or s u bj ects i n Gr o u ps 1 a n d 2 t he fi nal safet y assess me nts will be perf or me d a p pr o xi matel y 6 m o nt hs after 
a d mi nistrati o n of t he T D V b o oster or place b o at Visit 5 .  
Data c ollecti o n will be b y electr o nic Case Re p ort F or m (e C R F).  
Pri m ar y O bjecti ves:  
•  
T o descri be a nti b o d y persiste nce f or eac h of t he 4 de n g ue ser ot y pes f or u p t o 6 3  m o nt hs aft er t he first 
vacci nati o n i n t he pri mar y vac ci nati o n series f or s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o) a n d f or u p t o 
3 6 m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series f or s u bj ects fr o m pare nt trial D E N -3 0 4 
( U nite d States). 
•  
T o descri be t he i m pact of a T D V b o oster d ose vs place b o o n a nti b o d y res p o nse f or eac h of t he 4 de n g ue 
ser ot y pes at 1 m o nt h a n d 6 m o nt hs p ost a d mi nistrati o n of t he T D V b o oster or place b o . 
Sec o n d ar y O bjecti ves:  
I m m u n o ge nicity 
A nti b o d y P ersiste nce  
•  
T o descri be t he o verall tre n d i n a nti b o d y deca y f or all 4 de n g ue ser ot y pes fr o m val ues o btai ne d after t he 
pri mar y vacci nati o n series i n t he pare nt trials t hr o u g h 6 3  m o nt hs after t he first vacci nati o n i n t he pri mar y 
vacci nati o n series f or s u bj ects fr o m pare nt trial D E N -3 1 5 ( Me xic o) a n d t hr o u g h 3 6 m o nt hs after t he first 
vacci nati o n i n t he pri mar y vac ci nati o n series f or s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nit e d States) . 
I m pact of a T D V B o oster D ose 
•  
T o descri be t he i m pact of a T D V b o oster o n a nti b o d y res p o nse f or eac h of t he 4 de n g ue s er ot y pes f or u p t o 
6 9  m o nt hs f oll o wi n g t he first vacci nati o n i n t he pri mar y vac ci nati o n series f or s u bj ects fr o m pare nt trial 
D E N -3 1 5 ( Me x ic o) a n d f or u p t o 4 2 m o nt hs f oll o wi n g t he first vacci nati o n i n t he pri mar y vacci nati o n series 
f or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States).  
S afety  
•  
T o descri be t he l o n g -ter m safet y of T a ke da’s T D V f or u p t o 6 3  m o nt hs i n pre vi o usl y vacci nate d s u bj ects 
fr o m pare nt trial D E N-3 1 5 ( Me xic o) a n d f or u p t o 3 6 m o nt hs i n pre vi o usl y vacci nate d s u bj ects fr o m pare nt 
trial D E N-3 0 4 ( U nite d States).  
•  
T o assess safet y f or 6 m o nt hs f oll o wi n g a d mi nistrati o n of t he T D V b o oster or place b o i n Gr o u ps 1 a n d 2, 
res pecti vely . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 5 5  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
E x pl or at or y O bjecti ves:  
A p plica ble t o s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o o nl y):  
•  
T o e val uate as pects of t he l o n g -ter m h u m oral i m m u ne res p o nse t o T a ke da’s T D V i n all s u bj ects at 
6 3  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trial ( D E N-3 1 5) ; t his is 
i ncl usi ve of, b ut n ot restricte d t o, a n assess me nt of t he a nti-de n g ue N o n -Str uct ural pr otei n 1 ( N S 1) a nti b o d y 
res p o nse. 
A p plica ble t o s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nite d St ates o nl y):  
•  
T o e val uate as pects  of t he l o n g -ter m h u m oral i m m u ne res p o nse t o T a ke d a’s T D V i n all s u bj ects at 3 6 
m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trial  ( D E N-3 0 4) , a n d i n t he 
C MI s u bset at 1 m o nt h a n d 6 m o nt hs p ost b o oster i n t he c urre nt tr ial; t his is i ncl usi ve of, b ut n ot restricte d 
t o, a n assess me nt of t he a nti-de n g ue N S 1 a nti b o d y res p o nse.  
•  
T o e val uate as pects of t he l o n g -ter m cell-me diate d i m m u ne res p o nse t o T a ke da’s T D V u p t o 3 6 m o nt hs after 
t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trial ( D E N-3 0 4) a n d at 1 m o nt h a n d 
6  m o nt hs p ost b o oster i n t he c urre nt trial; t his is i ncl usi ve of, b ut n ot restricte d t o, t he ma g nit u de 
(I nterfer o n-ga m ma E nz y me -Li n ke d I m m u n os p ot [I F N -γ E LI S p ot]) of t he l o n g -ter m T cell-me diate d 
i m m u ne res p o nse t o T D V ( C MI s u bset o nl y). 
S u bject P o p ul ati o n:  
Healt h y S u bj ects: yes  
A ge Ra n ge: ≥1 3 t o ≤6 3 years  
Pla n ne d N u m ber of S u bj ects: u p t o 6 0 0  
Pla n ne d N u m ber of Trial Ar ms: A si n gle o pe n ar m u p t o Visit 3 a n d t w o ar ms t hereafter t hr o u g h t he e n d of trial, 
ra n d o mize d i n a 1: 1 rati o stratifie d b y pare nt trial a n d ser ost at us at baseli ne i n t he pare nt trials 
I ncl usi o n Criteri a at E ntr y: 
1.  T he s u bj ect is a ge d ≥1 3 a n d ≤6 3 years at e ntr y i nt o t he c urre nt trial.  
2.  Male or fe male s u bj ects (irres pecti ve of ser ostat us at b aseli ne i n t he pare nt trial s) w h o recei ve d at least o ne 
d ose of T a ke d a’s T D V i n t he pare nt trials a n d ha ve data fr o m at least o ne bl o o d dra w p ost -vacci nati o n . 
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 his 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 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 bj ect/t he s u bj ect’s L A R  si g ns a n d dates a writte n i nf or me d c o nse nt/ pe diatric asse nt f or m a n d a n y 
re q uire d pri vac y a ut h orizati o n pri or t o t he i nitiati o n of a n y trial pr oce d ures a n d after t he nat ure of t he 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 me nts. Asse nt is o btai ne d fr o m t he s u bj ect w here 
re q uire d. 
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 t he f oll o w -u p.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 5 6  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
E xcl usi o n Criteri a at E ntr y:  
A n y s u bj ect 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 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. 
2.  S u bj ects i n v ol ve d i n t he trial c o n d uct or t heir first -de gree relati ves.  
3.  S u bj ects t hat, i n t he o pi ni o n of t he i n vesti gat or, are n ot me di call y eli gi ble t o pr o vi de bl o o d sa m ples.  
4.  S u bj ects wit h a pr ol o n ge d peri o d  of ha bitati o n ( ≥1 year) i n a de n g ue e n de mic area wit hi n t he 2 years pri or t o 
Visit 1.  
5.  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 i ncl u di n g de n g ue ( ot her 
t ha n T a ke d a’s T D V) , yell o w fe ver ( Y F), J a pa nese e nce p halitis (J E) vir uses or tic k-b or ne e nce p halitis.  
6.  P artici pati o n i n a n y cli nical tri al is all o we d, o n c o n diti o n t hat n o i n vesti gati o nal pr o d uct is a d mi nistere d 
wit hi n 3 0 da ys pri or t o b l o o d sa m pli n g i n t he c urre nt trial. 
7.  S u bj ects wit h a n y ill ness, or a hist or y of a n y 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 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 . 
B o oster Eli gi bilit y:  
A n y s u bj ect w h o meets a n y of t he f oll o wi n g criteria at Visit 3 will n ot q ualif y f or ra n d o mi zati o n t o Gr o u p 1 or 2 
t o recei ve t he T D V b o oster or place b o, res pecti vel y: 
1.  S u bj ects f or w h o m b aseli ne ser ostat us is n ot defi ne d i n t he p are nt trials. 
2.  S u bj ects wit h a k n o w n h y pers e nsiti vit y or aller 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).  
3.  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 o r der, seiz ure dis or der or 
ne ur o -i nfla m mat or y disease (e g, G uillai n-B a rré s y n dr o me). 
4.  S u bj ects wit h a n y ill ness, or a hist or y of a n y 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 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.  
5.  K n o w n or s us pecte d i m pa ir 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 Visit 3; use of i n hale d, i ntra nasal, or t o pical 
c ortic oster oi d s is 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 Visit 3 . 
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 
a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3; 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.  
d)  Recei pt of i m m u n osti m ula nts wit hi n 6 0 da ys pri or t o Visit 3.  
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 Visit 3 . 
f) 
K n o w n h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n or HI V -relate d disease. 
g)  He p atitis C vir us i nfecti o n.  
h)  Ge netic i m m u n o deficie nc y.  
6.  A b n or malities of s ple nic or t h y mi c f u ncti o n.  
7.  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. 
8.  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 di a betes, car diac, re nal, or he patic disease).  
9.  S u bj ects wit h b o d y mass i n de x ( B MI) greater t ha n or e q ual t o 3 5 k g/ m 2 ( = wei g ht i n k g/[ hei g ht i n meters 2]). 
1 0.  S u bj ects w h o ha ve recei ve d a n y ot her vacci nes wit hi n t he 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 T D V  b o oster or place b o a d mi nistrati o n.  
1 1.  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.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 5 7  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
1 2.  Fe male s u bj ects w h o are pre g na nt or breastfee di n g.  
1 3.  Fe male s u bj ects of c hil d -beari n g p ote ntial 1  w h o are se x uall y acti ve wit h me n, 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 ds2 f or at least 2 m o nt hs pri or t o Visit 3 . 
1 4.  Fe male s u bj ects of c hil d beari n g p ote ntial w h o are se x uall y a cti 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” f or u p t o 6 wee ks after a d mi nistrati o n of t he T D V  b o oster or place b o at Visit 3 . 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 or breastfee d d uri n g t his peri o d . 
1 5.  A n y p ositi ve or i n det er mi nate pre g na nc y test.  
1 6.  S u bj ects wit h hist or y of c urre nt or pre vi o us i nfecti o n wit h a fla vi vir us s uc h as de n g ue, Zi ka, Y F, J E, West 
Nile fe ver, tic k -b or ne e nce p halitis or M urra y Valle y e nce p halitis a n d s u bj ects wit h a pr ol o n ge d peri o d  of 
ha bitati o n ( ≥1 ye ar) i n a de n g ue e n de mic area d uri n g trial c o n d uct . 
T here ma y be i nsta nces w he n s u bj ects meet all t he criteria f or ‘b o oster eli gi bilit y ’ 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 ns[s] or 
vacci ne[s]). U n der t hese circ u msta nces, eli gi bilit y f or t he T D V  b o oster/ place b o 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, if ‘b o oster eli gi bilit y ’ ha s 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.  
Tri al V acci ne  a n d Pl ace b o : 
I nvesti g ati o n al v acci ne 
T he i n vesti gati o nal vacci ne is T a ke d a’s T D V , a tetra vale nt v acci ne c o m prise d of 1 m olec ul arl y c haracterize d, 
atte n uate d de n g ue vir us strai n ( T D V -2), a n d 3 rec o mbi na nt d e n g ue vir us strai ns 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 a ke d a’s T D V  is a l y o p hilize d vacci ne t hat will be rec o nstit ute d i n T D V dil ue nt ( 3 7 m M s o di u m c hl ori de 
s ol uti o n) pri or t o a d mi nistratio n.  
Pl ace b o  
T he place b o is n or mal sali ne f or i nj ecti o n ( 0. 9 % sali ne).  
R o ute of a d mi nistr ati o n  
S C 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 bet wee n 4 2  m o nt hs a n d 4 8  m o nt hs f or s u bj ects fr o m pare nt 
trial D E N -3 1 5 ( Me xic o), a n d bet wee n 1 5 m o nt hs a n d 2 1 m o nt hs f or s u bj ects fr o m pare nt trial D E N-3 0 4 
( U nite d States) . 
Criteri a f or E v al u ati o n a n d A n al yses:  
N ote, f or all s u bj ects Visit 1 ( Da y 1 [ M 0]) a n d Visit 2 ( Da y 3 6 0 [ M 1 2]) c orres p o n d t o 2 1  m o nt hs a n d 3 3  m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trial. F or s u bj ects fr o m pare nt 
trial D E N -3 1 5 ( Me xic o), Visit 3 ( Da y 1 2 6 0 [ M 4 2]), Visit 4 ( Da y 1 2 9 0 [ M 4 3]), a n d Visit 5 ( Da y 1 4 4 0 [ M 4 8 ]) i n 
t his trial c orres p o n d t o 6 3 m o nths, 6 4 m o nt hs, a n d 6 9  m o nt hs after t he first vacci nati o n i n t he pri mar y 
vacci nati o n series, res pecti vel y. F or s u bj ects fr o m pare nt tri al D E N -3 0 4 ( U nite d States), Visit 3 ( Da y 4 5 0 
[ M 1 5]), Visit 4 ( Da y 4 8 0 [ M 1 6]), a n d Visit 5 ( Da y 6 3 0 [ M 2 1]) i n t his trial c orres p o n d t o 3 6 m o nt hs, 3 7 m o nt hs, 
a n d 4 2 m o nt hs after t he first v acci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trial, res pecti vel y.  
                                                 
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:  me n o pa usal (at least 2 
years pre vi o usl y),  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 H or m o nal c o ntrace pti ves (e g, oral, i nj ecti o n, tra ns der mal patc h, i m pla nt, cer vical ri n g), barrier met h o d (c o n d o m 
wit h s per mici de or dia p hra g m wit h s per mici de)  e ver y ti me d uri n g i nterc o urse, i ntra uteri ne de vice , m o n o ga m o us 
relati o ns hi p wit h a vasect o miz e 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 
Visit  3. 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 m ust be a p pr o ve d 
b y t he a p pr o priate et hics c o m mittee . 
 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 5 8  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Pri m ar y e n d p oi nts:  
•  
Ge o metric mea n titers ( 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 a n d 
ser o p ositi vit y rates ( % of s u bj ects wit h reci pr ocal ne utralizi n g titer ≥1 0) f or eac h of t he 4 de n g ue ser ot y pes 
a n d m ulti ple ( 2, 3 or 4) at Visit 1, Visit  2,  a n d  Visit 3 (pri or t o a d mi nistrati o n of t he T D V b o oster or place b o 
f or s u bj ects ra n d omize d t o Gr o u ps 1 a n d 2, res pecti vel y) s u m marize d f or all s u bj ects, f or all s u bj ects b y 
pare nt trial, a n d f or all s u bj ects b y ser ostat us at baseli ne i n t he pare nt trials.  
•  
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 a n d sero p ositi vit y rates 
( % of s u bj ects wit h reci pr ocal ne utralizi n g titer ≥1 0) f or eac h of t he 4 de n g ue ser ot y pes a n d m ulti ple 
( 2, 3  or  4) at Visit 4 a n d Visit 5 f or s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 b y trial gr o u p, b y trial gr o u p a n d 
pare nt trial, a n d b y tr ial gr o u p a n d ser ostat us at baseli ne i n t he pare nt trials. 
Sec o n d ar y e n d p oi nts : 
I m m u n o ge nicit y e n d p oi nts 
A nti b o d y P ersiste nce  
•  
Ge o metric Mea n Rati o ( G M R) of ne utralizi n g a nti b o dies f or eac h of t he 4 de n g ue ser ot y pes f or all s u bj ects, 
f or all s u bj ects b y pare nt trial, a n d f or all s u bj ects b y ser ostat us at baseli ne i n t he pare nt trials f or:  
•  Visit 1 vs Visit 2.  
•  Da y 1 2 0 ( M o nt h 4) i n t he pare nt trials ( 4 m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n 
series i n t he pare nt trials) vs Visit 3 i n t he curre nt trial.  
•  Da y 2 7 0 ( M o nt h 9) i n t he pare nt trials ( 9 m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n 
series i n t he pare nt trials) vs Visit 1 a n d Visit 2 i n t he c urre nt trial.  
I m pact of a T D V B o oster D ose 
•  
G M R of ne utralizi n g a nti b o dies f or eac h of t he 4 de n g ue ser ot y pes f or s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 
2 b y trial gr o u p, b y trial gr o u p a n d pare nt trial, a n d b y trial gr o u p a n d ser ostat us at baseli ne i n t he pare nt 
trials f or: 
•  
Da y 1 2 0 ( M o nt h 4) i n t he pare nt trials ( 4 m o nt hs after t he fir st vacci nati o n i n t he pri mar y vacci nati o n 
series i n t he pare nt trials) vs Visit 4 i n t he c urre nt trial. 
•  
Visit 3  vs Visit 4.  
•  
Visit 3 vs Visit 5.  
•  
Visit 4 vs  Visit 5.  
•  
Da y 1 2 0 ( M o nt h 4) i n t he pare nt trials ( 4 m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n 
series i n t he pare nt trials) vs Visit 5 i n t he c urre nt trial. 
Safet y  e n d p oi nts  
•  
Fre q ue nc y a n d se verit y of s oli cite 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) , 
a n d s olicite d s yste mic A Es f or 1 4 da ys ( da y of vacci na ti o n + 1 3 da ys) f oll o wi n g a d mi nistrati o n of t he T D V 
b o oster or place b o at Visit 3  b y trial gr o u p.  
•  
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) f oll o wi n g 
a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3  b y trial gr o u p.  
•  
P erce nta ge of s u bj ects wit h a n y M A A Es f oll o wi n g a d mi nistr ati o n of t he T D V b o oster or place b o fr o m 
Visit  3  t hr o u g h Visit 5 b y trial gr o u p. 
•  
P erce nta ge of s u bj ects wit h a n y S A Es fr o m Visit 1 t hr o u g h Visit  3  pri or t o a d mi nistrati o n of t he T D V 
b o oster or place b o.  
•  
P erce nta ge of s u bj ects wit h a n y S A Es f oll o wi n g a d mi nistrati o n of t he T D V b o oster or place b o fr o m Visit 3 
t hr o u g h Visit 5 b y trial gr o u p. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 5 9  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
E x pl or at or y e n d p oi nts:  
A p plica ble t o s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o o nl y):  
•  
T he assess me nt of t he l o n g -ter m h u m oral res p o nse t o T D V will i ncl u de, b ut is n ot restrict e d t o, t he 
meas ure me nt of t he a nti -de n g ue N S 1 a nti b o d y res p o nse b y e nz y me -li n ke d i m m u n os or be nt assa y (a vera ge 
c o nce ntrati o n [relati ve u nits/ m L] of a nti -de n g ue N S 1 a nti b o dies f or eac h of t he 4 de n g ue ser ot y pes) usi n g 
bl o o d sa m ples c ollecte d fr o m all s u bj ects at Visit 3 . A d diti o nal e x pl orat or y tec h ni q ues ma y be a d de d as t he 
fiel d e v ol ves. 
A p plica ble t o s u bj ects fr o m  pare nt trial D E N -3 0 4 ( U nite d St ates o nl y):  
•  
T he assess me n t of t he l o n g-ter m h u m oral res p o nse t o T D V will i ncl u de, b ut is n ot restrict e d t o, t he 
meas ure me nt of t he a nti -de n g ue N S 1 a nti b o d y res p o nse b y e nz y me -li n ke d i m m u n os or be nt assa y (a vera ge 
c o nce ntrati o n [relati ve u nits/ m L] of a nti -de n g ue N S 1 a nti b o dies f or ea c h of t he 4 de n g ue ser ot y pes) usi n g 
bl o o d sa m ples c ollecte d fr o m all s u bj ects at Visit 3, a n d fr o m s u bj ects i n t he C MI s u bset at Visit 4 a n d 
Visit  5. A d diti o nal e x pl orat or y tec h ni q ues ma y be a d de d as t he fiel d e v ol ves.  
•  
T he assess me nt of t he l o n g -ter m cell-me diate d res p o nse t o T D V will i ncl u de, b ut is n ot restricte d t o, t he 
fre q ue nc y ( perce nta ge of s u bj ects) a n d ma g nit u de ( n u m ber of S p ot F or mi n g Cells [ S F C]/ 1 0 6 P B M C) of 
I F N-γ E LI S p ot res p o nses t o T D V usi n g bl o o d sa m ples c olle cte d fr o m s u bj ects i n t he C MI s u b set at Visit 1, 
Visit 2, Visit 3, Visit 4, a n d Visit 5. Cell ular i m m u ne res p o ns e is defi ne d as a n I F N -γ E LI S p ot res p o nse t hat 
is > 3 ti mes hi g her c o m pare d wit h bac k gr o u n d ( n o pe pti de) a n d ≥5 0 s p ots per 1 0 6 P B M C. A d diti o nal 
e x pl orat or y tec h ni q ues ma y be a d de d as t he fiel d e v ol ves ( C MI s u bset o nl y) . 
St atistic al C o nsi der ati o ns:  
T he f oll o wi n g a nal ysis sets are defi ne d f or t his trial:  
All Scree ne d: All s u bj ects w h o a gree d t o partici pate i n t he c urre nt trial.  
All Scree ne d -B o oster:  All s u bj ects w h o a gree d t o partici pate i n t he c urre nt trial a n d w h o were scree ne d f or 
‘ b o oster eli gi bilit y’ t o deter mi ne if t he y were  eli gi ble t o g o o n t o be ra n d o mize d t o Gr o u p 1 or Gr o u p 2.  
R a n d o mize d Set -B o oster:  All s u bj ects ra n d o mize d at Visit 3 re gar dless of w het her t he y r ecei ve d t he trial 
vacci nati o n i n t he c urre nt trial. S u bj ects i n t his set will be s u m marize d acc or di n g t o ra n d o mize d treat me nt.  
S afet y Set ( S A F): All s u bj ects w h o a gree d t o partici pate i n t he c urre nt trial a n d w h o recei ve d at least o n e d ose 
of T a ke d a’s T D V i n t he pare nt trial s. 
S afet y Set -B o oster ( S A F -B): All s u bj ects w h o recei ve d at least o ne d ose of T a ke da’s T D V i n t he pare nt trial s 
a n d w h o recei ve d t he T D V b o oster or place b o i n t he c urre nt trial.  
F ull A n al ysis Set ( F A S):  All s u bj ect s w h o recei ve d at least o ne d ose of T a ke da’s T D V i n t he pare nt trials a n d 
f or w h o m t here is at least o ne vali d f oll o w-u p meas ure me nt u p t o Visit 3 f or i m m u n o ge nicit y assess me nts i n t he 
c urre nt trial.  
F ull A n al ysis Set -B o oster ( F A S -B):  All s u bj ects w h o rece i ve d at least o ne d ose of T a ke da’s T D V i n t he pare nt 
trials, t he T D V b o oster or place b o i n t he c urre nt trial, a n d f or w h o m t here is at least o ne vali d f oll o w-u p 
meas ure me nt after a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3  f or i m m u n o ge nicit y assess me nts i n 
t he c urre nt trial. 
Per Pr ot oc ol Set ( P P S):  All s u bj ects fr o m t he F A S w h o recei ve d t w o d oses of T a ke da’s T D V i n t he pare nt trials 
wit h n o ne w maj or pr ot oc ol vi olati o ns pri or t o a d mi nistrati o n of t he b o oster or place b o at Visit 3  t hat c o ul d 
p ote ntiall y c o nf o u n d t he pri mar y e n d p oi nts i n t he c urre nt tri al.  
Per Pr ot oc ol Set -B o oster ( P P S -B):  All s u bj ects fr o m t he F A S -B w h o recei ve d t w o d oses of T a ke da’s T D V i n 
t he pare nt trials wit h n o ne w maj or pr ot oc ol vi olati o ns after a d mi nistrati o n of t he T D V b o oster or place b o at 
Visit 3 t hat c o ul d p ote ntiall y c o nf o u n d t he pri mar y e n d p oi nts i n t he c urre nt trial.  
T he maj or pr ot oc ol vi olati o n criteri o n will be defi ne d as part of a data re vie w pri or t o a nal ysis. T he cate g ories of 
ne w maj or pr ot oc ol vi olati o ns i ncl u d e: ( 1) n ot meeti n g select e d e ntr y criteria, ( 2) recei vi n g t he wr o n g trial 
vacci nati o n at Visit 3  (s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 o nl y), ( 3) recei vi n g pr o hi bit e d vacci nati o ns or 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 6 0  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
t hera pies (s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 o nl y), ( 4) perf or mi n g Visit 4 i na d missi bl y o utsi de t he visit 
wi n d o w (s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 o nl y), a n d ( 5) ot her maj or pr ot oc ol vi olati o ns t hat ma y be 
i de ntifie d d uri n g data re vie ws. 
N ote, f or all s u bj ects Visit 1 ( Da y 1 [ M 0]) a n d Visit 2 ( Da y 3 6 0 [ M 1 2]) c orres p o n d t o 2 1  m o nt hs a n d 3 3 m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trial. F or s u bj ects fr o m pare nt trial 
D E N -3 1 5 ( Me xic o), Visit 3 ( Da y 1 2 6 0 [ M 4 2]), Visit 4 ( Da y 1 2 9 0 [ M 4 3]), a n d Visit 5 ( Da y 1 4 4 0 [ M 4 8 ]) i n t his 
trial c orres p o n d t o 6 3 m o nt hs, 6 4 m o nt hs, a n d 6 9  m o nt hs aft er t he first vacci nati o n i n t he pri mar y vacci nati o n 
series, res pecti vel y. F or s u bj ects fr o m pare nt trial D E N -3 0 4 ( U nite d States), Visit 3 ( Da y 4 5 0 [ M 1 5]), Visit 4 
( Da y 4 8 0 [ M 1 6]), a n d Visit 5 ( Da y 6 3 0 [ M2 1]) i n t his trial c orres p o n d t o 3 6 m o nt hs, 3 7  m o nt hs, a n d 4 2 m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trial, res pecti vel y.  
A nal ysis of de m o gra p hics a n d ot her B aseli ne c haracteristics  
A ge, ge n der, race, a n d ot her b aseli ne c haracteristics (i ncl u di n g a ge at i nf or me d c o nse nt i n t he pare nt trial) will 
be s u m marize d descri pti vel y f or all e nr olle d s u bj ects u p o n e ntr y i nt o t he c urre nt trial.  
I m m u n o ge nicit y e val uati o n 
F or t he pri mar y a n d sec o n dar y i m m u n o ge nicit y e n d p oi nts ( ie, G M Ts of ne utralizi n g a nti b o dies a n d 
ser o p ositi vit y rates f or eac h of t he 4 de n g ue ser ot y pes a n d m ulti ple [ 2, 3 or 4]), descri pti ve statistics a n d 9 5 % CIs 
will b e pr o vi de d f or eac h a p plica ble visit ( Visit 1, Visit 2, Visit 3, Visit 4, a n d Visit 5 i n t he c urre nt trial , a n d f or 
Da y 1 2 0 [ M o nt h 4] a n d Da y 2 7 0 [ M o nt h 9] i n b ot h t he pare nt trials [ w hic h c orres p o n ds t o 4  m o nt hs a n d 
9  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trials, res pecti vel y]) . 
F or t he visit c o m paris o ns G M Rs will be s u m marize d descri pti vel y, i ncl u di n g 9 5 % CIs.  
Ser o p ositi vit y is defi ne d as a reci pr ocal ne utralizi n g titer ≥1 0. Ot her i m m u n o ge nicit y meas ure me nts o btai ne d at 
baseli ne a n d a n y p ost -vacci nati o n visits i n t he pare nt trials ma y be accesse d fr o m  data b ases t o c o ntri b ute t o 
desi g nate d s u m maries of i m m u n o ge nicit y e n d p oi nts o ver ti me f oll o wi n g vacci nati o n.  
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/ P P S -B; se nsiti vit y a nal ys es ma y be pr o vi de d 
base d o n t he F A S/ F A S -B.  
Si milar descri pti ve a nal ys es as f or t he pri mar y i m m u n o ge ni cit y e n d p oi nt will be pr o vi de d f or t he e x pl orat or y 
e n d p oi nts f or eac h a p plica ble assa y at all rele va nt ti me p oi nts, base d o n t he P P S/ P P S -B. S u p p orti ve  a nal yses 
base d o n t he F A S/ F A S -B ma y als o be pr o vi de d f o r selecte d e n d p oi nts. 
F urt her details o n t he statistical a nal ysis i ncl u di n g e x pl orat or y e n d p oi nts will be pr o vi de d i n t he statistical 
anal ysis p la n (S A P ). 
Safet y e val uati o n  
All s u m maries of safet y data will b e base d o n s u bj ects i n t he S A F/ S A F -B.  
S olicite d A Es  
Prese nce a n d se verit y ( Gra d e) of s olicite d l o cal reacti o ns (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) a n d 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 b y diar y car d f or 7 da y s a n d 1 4 da ys, res pecti vel y, f oll o wi n g a d mi nistrati o n of t he T D V  b o oster or 
place b o.  
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 ec ts wit h l ocal (i nj ecti o n site) reacti o ns a n d s yste mic 
A Es will be s u m marize d b y tri al gr o u p a n d e ve nt se verit y f o r eac h da y f oll o wi n g a d mi nistr ati o n of t he T D V  
b o oster or place b o ( 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 o rte d 
e x perie nci n g eac h e ve nt will als o be pr o vi 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 a n d Da y 1 5  (after 
a d mi nistrati o n of t he T D V  b o oster or place b o), res pecti vel y, will be assesse d se paratel y. U nless ot her wise 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 6 1  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
s pecifie d t hese reacti o ns/ A Es will n ot b e i ncl u de d i n t he a nal yses/ta b ulati o ns of u ns olicite d A Es a n d will ha ve 
se p arate listi n gs. 
U ns olicite d A Es  
U ns olicite d A Es will be s u m marize d b y trial gr o u p f or 2 8 da ys f oll o wi n g a d mi nistrati o n of t he T D V  b o oster or 
place b o ( 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 latest versi o n of t he Me dical 
Dicti o nar y f or Re g ulat or y Acti viti es ( 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. A Es lea di n g t o trial wit h dr a wal will be s u m marize d u p t o Visit 3  
(pre -vacci nati o n) a n d t hereaft er ( p ost -vacci nati o n) b y trial gr o u p u p t o Visit 5 . 
U ns olicite d A Es will be ta b ulate d at eac h of t he f oll o wi n g le vels: o verall s u m mar y (s u bj ects wit h at least 1 A E), 
a n d b y S O C a n d P T. I n a d diti o n, 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 greater 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 vacci ne ( T D V b o oster or place b o ). S u bj ects 
re p orti n g m ore t ha n 1 occ urre nce f or t he ter m (le vel) bei n g s u m marize d will be c o u nte d o nl y o nce.  
M A A Es  
M A A Es will be c ollecte d f or s u bj ects ra n d o mize d t o Gr o u p 1 a n d Gr o u p 2 a n d will be prese nte d b y trial gr o u p 
fr o m Visit 3 t hr o u g h Visit 5. M A 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 S O C a n d P T f or eac h 
trial gr o up.  
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 u p t o Visit 3  (pre -vacci nati o n ) a n d t hereafter ( p ost -vac ci nati o n) b y trial gr o u p u p t o Visit 5 . 
S a m ple Size J ustific ati o n:  
T his trial is desi g ne d t o be descri pti ve a n d is n ot base d o n testi n g f or mal n ull h y p ot heses. T heref ore, t he sa m ple 
size was n ot d eter mi ne d base d o n f or mal statistical p o wer calc ulati o ns.  T he n u m ber of s u bj ects is c o nsi dere d t o 
be s ufficie nt f or t he e val uati o n of t he o bj ecti ves of t he trial.  
I nteri m A n al ysis: 
D ue t o si g nifica nt d ela ys ( of > 2 years) t o b o oster a d mi nistrati o n f or s u bj ects fr o m pare nt tri al D E N-3 1 5 
( Me xic o), a n i nteri m a nal ysis (I A) of t he safet y a n d i m m u n o ge nicit y data c ollecte d at trial sites i n t he U nite d 
States is pla n ne d w he n all s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States) ha ve c o m plete d t heir last trial visit 
( Visit 5 [ Da y 6 3 0 ( M 2 1)]). T his I A will be perf or me d i n a n u n bli n de d ma n ner a n d will i ncl u de t he necessar y 
ste ps t o e ns ure t hat n o data b ase m o dificati o ns are ma de after u n bli n di n g f or s u bj ects at trial sites i n t he U nite d 
States. U n bli n di n g of s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o) will occ ur after all s u bj ects at trial sites i n 
Me xic o ha ve c o m plete d t heir l ast trial visit ( Visit 5 [ Da y  1 4 4 0 ( M 4 8 )]) a n d t he trial data b ase has bee n  
l oc ke d. N o m o dificati o ns t o t he trial  are pla n ne d  base d o n t he res ults of t his  I A. A n i nteri m C S R of data fr o m 
pare nt trial D E N -3 0 4 ( U nite d States) will n ot be pre pare d ; all trial res ults will be re p orte d i n t h e fi nal C S R. M ore 
details re gar di n g t he I A will b e  pr o vi de d i n t he S A P.  
D at a M o nit o ri n g C o m mittee:  
A Data M o nit ori n g C o m mitte e ( 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 3 Versi o n 5. 0  (2 2  A u g ust  2 0 2 2 ) 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s  Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 6 2  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
2. 1  
Sc he d ule of Tri al Pr oce d ures  
Visit  
B y P are nt Tri al  
( D E N-3 0 4/ D E N -3 1 5)  
1  
2 ( a) 
3 ( b) 
4 (c) 
5 (c) 
( D a y 1[ M 0]/ 
D a y 1[ M 0])  
( D a y 3 6 0 [ M 1 2]/ 
D a y 3 6 0 [ M 1 2])  
( D a y 4 5 0 [ M 1 5]/ 
D a y 1 2 6 0 [ M 4 2])  
( D a y 4 8 0 [ M 1 6]/ 
D a y 1 2 9 0 [ M 4 3])  
( D a y 6 3 0 [ M 2 1]/ 
D a y 1 4 4 0 [ M 4 8])  
Visit Wi n d o w ( D a ys)  
-1 5/ + 7 5  
( Li n ke d t o 
P are nt D a y 1)  
-4 5/ + 4 5  
( Li n ke d t o 
Visit 1)  
-4 5/ + 4 5  
( Li n ke d t o 
Visit 1)  
-1 2 0/ + 1 2 0  
( Li n ke d t o 
Visit 1)  
-1/ + 7  
( Li n ke d t o 
Visit 3)  
-0/ + 6 0  
( Li n ke d t o 
Visit 3)  
A p plic a ble t o S u bjects F r o m P are nt 
T ri al  
D E N -3 0 4  
D E N -3 1 5  
D E N -3 0 4  
D E N -3 1 5  
D E N -3 0 4  
D E N -3 1 5  
D E N -3 0 4  
D E N -3 1 5  
D E N -3 0 4  
D E N -3 1 5  
Site visit  
X  
X  
X  
X  
X  
P h o ne c o ntact  
X ( d) 
X ( d) 
 
 
 
Si g ne d I nf or me d C o nse nt/  
P e diatric Asse nt F or m (e) 
X  
 
X  
 
 
Eli gi bilit y criteria  
X  (f) 
 
X ( g) 
 
 
Ra n d o mizati o n  ( h) 
 
 
X  
 
 
De m o gra p hics  
X  
 
 
 
 
Pre g na nc y test (i) 
 
 
X  
 
 
Me dical hist or y u p date  
X (j) 
 
X (c) 
 
 
Pri or me dicati o n u p date  
X (j) 
 
X (c) 
 
 
C o nc o mita nt me dicati o n u p date ( k) 
 
X  
X (c) 
X  
 
C o nc o mita nt vacci nati o n u p date (l) 
X  
X  
X  
X  
X  
C o m plete p h ysical e xa mi nati o n ( m) 
X  
 
X  (c) 
 
 
T ar gete d p h ysical e xa mi nati o n  ( n) 
 
 
 
X  
X  
Vital si g ns ( o) 
X  
X  
X  
X  
X  
Re vie w of s yste ms  
 
 
X (c) 
 
X  
Pre g na nc y a v oi da nce g ui da nc e ( p) 
 
X  
X (c) 
X  
 
I n vesti gati o nal pr o d uct ( q) 
a d mi nistere d b y S C i nj ecti o n  
 
 
X (c) 
 
 
I nj ecti o n site e val uati o n (r) 
 
 
X (c) 
 
 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s  Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 6 3  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Visit  
B y P are nt Tri al  
( D E N-3 0 4/ D E N -3 1 5)  
1  
2 ( a) 
3 ( b) 
4 (c) 
5 (c) 
( D a y 1[ M 0]/ 
D a y 1[ M 0])  
( D a y 3 6 0 [ M 1 2]/ 
D a y 3 6 0 [ M 1 2])  
( D a y 4 5 0 [ M 1 5]/ 
D a y 1 2 6 0 [ M 4 2])  
( D a y 4 8 0 [ M 1 6]/ 
D a y 1 2 9 0 [ M 4 3])  
( D a y 6 3 0 [ M 2 1]/ 
D a y 1 4 4 0 [ M 4 8])  
Visit Wi n d o w ( D a ys)  
-1 5/ + 7 5  
( Li n ke d t o 
P are nt D a y 1)  
-4 5/ + 4 5  
( Li n ke d t o 
Visit 1)  
-4 5/ + 4 5  
( Li n ke d t o 
Visit 1)  
-1 2 0/ + 1 2 0  
( Li n ke d t o 
Visit 1)  
-1/ + 7  
( Li n ke d t o 
Visit 3)  
-0/ + 6 0  
( Li n ke d t o 
Visit 3)  
A p plic a ble t o S u bjects F r o m P are nt 
T ri al  
D E N -3 0 4  
D E N -3 1 5  
D E N -3 0 4  
D E N -3 1 5  
D E N -3 0 4  
D E N -3 1 5  
D E N -3 0 4  
D E N -3 1 5  
D E N -3 0 4  
D E N -3 1 5  
Diar y 
car d (s) 
Distri b uti o n  
 
 
X (c) 
 
 
Re vie w/c ollecti o n of 
s olicite d l ocal reacti o ns a n d 
s yste mic A Es 
 
 
X (c) 
X  
 
U ns olicite d A Es (t) 
 
 
X (c) 
X  
 
M A A Es 
( u) 
 
 
X (c) 
X  
X  
S A Es a n d A Es lea di n g t o s u bj ect 
disc o nti n uati o n or wit h dra wal ( v) 
X  
X  
X  
X  
X  
Criteria f or dela y of bl o o d sa m pli n g  
X  
X  
X  
X  
X  
Bl o o d dra w ( 1 0 m L) ( w) 
X  
X  
X  
X  
X  
Bl o o d dra w ( 4 0 m L) ( w) 
 
 
X  
 
 
A d diti o nal bl o o d dra w ( 1 0 m L C MI 
s u bset o nl y, n =  5 0) ( x) 
 
 
 
X  
X  
A d diti o nal bl o o d dra w ( 4 0 m L C MI 
s u bset o nl y, n =  5 0) ( x) 
X  
X  
X  
X  
X  
A b bre viati o ns: A E, a d verse e ve nt; C MI, cell -me diate d i m m u nit y; M, M o nt h; M A A E,  me dicall y atte n de d a d verse e ve nt; N A, n ot a p plica ble; S A E, seri o us 
a d verse e ve nt; S C,  s u bc uta ne o us. 
N ote, f or all s u bj ects Visit 1 ( Da y 1 [ M 0]) a n d Visit 2 ( Da y 3 6 0 [ M 1 2]) c orres p o n d t o 2 1  m o nt hs a n d 3 3 m o nt hs after t he first vacci nati o n i n t he pri mar y 
vacci nati o n series i n t he pare nt trial. F or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o), Visit 3 ( Da y 1 2 6 0 [ M 4 2]), Visit 4 ( Da y 1 2 9 0 [ M 4 3]), a n d Visit 5 
( Da y 1 4 4 0 [ M 4 8 ]) i n t his trial c orres p o n d t o 6 3 m o nt hs, 6 4 m o nt hs, a n d 6 9  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series, res pecti vel y. F or 
s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d S tates), Visit 3 ( Da y 4 5 0 [ M 1 5]), Visit 4 ( Da y 4 8 0 [ M 1 6]), a n d Visit 5 ( Da y 6 3 0 [ M 2 1]) i n t his trial c orres p o n d t o 3 6 
m o nt hs, 3 7  m o nt hs, a n d 4 2 m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n s eries i n t he pare nt trial, res pecti vel y.  
 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 6 4  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
(a) At Visit 2, s u bj ects will be re mi n de d of a n y iss ues relati n g t o a d mi nistrati o n of/ or eli gi bilit y f or t he u pc o mi n g 
b o oster d ose at Visit 3. T his i ncl u des, b ut is n ot li mite d t o, t he c ollecti o n of a n y S A Es a n d a n y A Es lea di n g t o 
s u bject disc o nti n uati o n or wit h dra wal, a re vie w of pr o hi bite d t hera pies, pre g na nc y a v oi da nce g ui da nce a n d 
i nf or mati o n o n acce pta ble met h o ds of c o ntrace pti o n (f or fe male s u bj ects of c hil d beari n g a ge). 
( b) Visit 3 will be dela ye d u ntil D a y 1 2 6 0 (M 4 2) f or s u bj ect s fr o m pare nt trial D E N-3 1 5  ( Me xic o). 
(c) A p plica ble o nl y t o s u bj ects ra n d o mize d t o Gr o u p 1 or Gr o u p 2 at Visit 3.  
( d) A rete nti o n p h o ne call will be ma d e bet wee n Visits 1 a n d 2 o n Da y 1 8 0 ( M 6) t o mai ntai n c o ntact wit h t he 
s u bj ect/t he s u bj ect’s le gall y ac ce pta ble re prese ntati ve ( L A R) a n d t o re mi n d t he s u bj ect/t he s u bj ect’s L A R a b o ut 
t he u pc o mi n g site visit. A sec o n d rete nti o n p h o ne call will b e ma d e t o s u bj ects fr o m pare nt trial D E N-3 1 5 
( Me xic o) bet wee n Visits 2 a n d 3 o n Da y 5 4 0  ( M1 8 ). 
(e) Pri or t o t he s u bj ect 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 perf or me d; u p t o 
2 8  da ys pri or t o t he da y o f e nr oll me nt. A d olesce nts fr o m par e nt trial D E N-3 1 5 ( Me xic o) w h o bec o me 1 8 years 
of a ge d uri n g t he c o urse of t he trial will b e as ke d t o ret ur n t o t he i n vesti gati o nal site f or a n a d diti o nal site visit 
t o pr o vi de t he a p pr o priate writte n i nf or me d c o nse nt. T his s h o ul d be d o ne as s o o n as p ossi ble after t heir 1 8t h 
birt h da y. D ue t o c ha n ges i n t he trial desi g n i n Me xic o (P r ot oc ol A me n d me nt 3 , date d 2 2 A u g ust  2 0 2 2 ), all 
s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o) will n o w be as ke d t o re -c o nse nt usi n g a n  u p date d I C F or a n 
u p date d i nf or me d c o nse nt a n d pe diatric asse nt f or m , as a p plica ble, at Visit 3  bef ore a n y f urt her pr ot oc ol -
directe d pr oce d ures are perf or me d . A n oral s u m mar y of a n y maj or c ha n ges t hat ha ve bee n ma de t o t he st u d y 
will b e pr o vi de d t o t he s u bj ect a n d t he  s u bj ect’s L A R w here a p plica ble i n a d diti o n t o t he I C F/ Asse nt F or m; t his 
will b e d oc u me nte d i n t he me dical c hart as part of t he re -c o nse nt pr ocess. Re -c o nse nt date s h o ul d als o be 
d oc u me nte d i n t he electr o nic Case Re p ort F or m (e C R F).  
(f) After i nf or me d c o ns e nt has be e n o btai ne d, eli gi bilit y of t he s u bj ect will be assesse d b y re vi e w of 
i ncl usi o n/e xcl usi o n criteria f or trial e ntr y at Visit 1. 
( g) A re vie w of t he ‘ b o oster eli gi bilit y’ will be perf or me d pri or t o ra n d o mizati o n at Visit 3 . 
( h) Stratifie d b y pare nt  trial a n d s er ostat us at baseli ne i n t he par e nt trials. 
(i) F or fe male s u bj ects of c hil d beari n g p ote ntial, pre g na nc y testi n g ( uri ne) will b e perf or me d at Visit 3.  Res ults 
m ust b e c o nfir me d a n d d oc u me nte d as ne gati ve pri or t o a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3. 
A d diti o nal pre g na nc y tests ma y be perf or me d d uri n g t he trial if dee me d necessar y b y t he i n vesti gat or; w here t he 
res ults of a uri ne pre g na nc y test are i n d o u bt, a ser u m pre g na nc y test will be perf or me d t o verif y t he res ult.  
(j) A n y rele va nt i nf or mati o n c oll ecte d d uri n g t he pare nt trials will be accesse d via t he data b ase a n d u p date d as 
necessar y t hr o u g h o ut t he trial c o n d uct.  
( k) All 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 t he T D V b o oster or place b o at 
Visit 3 a n d 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 
Visit 3 ; 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 mo nt hs pri or t o Visit 3 ; 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 Visit 3.  
(l) A n y i nacti vate d vacci nes a d mi nistere d ≤1 4 da ys a n d a n y li ve atte n uate d vacci nes a d mi nist ere d ≤2 8 da ys pri or 
t o bl o o d sa m ple c ollecti o n or T D V b o oster/ place b o a d mi nistrati o n at Visit 3. 
( m) 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.  
( n) S u bj ects ma y u n der g o a tar get e d 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 ( Visit 1) 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.  
( o) 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.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 6 5  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
( p) S u bj ects  will be pr o vi de d wit h i nf or mati o n o n acce pta 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 at Visit 1 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 va. F urt her g ui da nce wit h res pect t o t he a v oi da nce of 
pre g na nc y will be pr o vi de d t o all fe male s u bj ects of c hil d beari n g p ote ntial at Visit 2 a n d t o all fe male s u bj ects 
of c hil d beari n g p ote ntial w h o are ra n d o mize d t o Gr o u p 1 or 2 at Visit  3, a n d at Visit 4.  Fe males of c hil d beari n g 
p ote ntial, w h o are ra n d o mize d t o Gr o u p 1 or 2 a n d are se x uall y acti ve, will als o be re mi n d e d t o a d here t o 
acce pta ble c o ntrace pti ve met h o ds f or u p t o 6 wee ks after T D V b o oster or place b o a d mi nistrati o n.  
( q) S u bj ects w h o meet  t he criteria f or ‘ b o oster eli gi bilit y’ a n d are s u bse q ue ntl y ra n d o mize d t o Gr o u p 1 or Gr o u p 2 
at Visit 3  will recei ve t he T D V b o oster or place b o, res pecti vel y. 
(r) I nj ecti o n site pai n, er yt he ma, a n d s welli n g assesse d b y trial staff f or 3 0 mi n utes p ost-vacc i nati o n. 
(s) Diar y car ds ( pa p er or electr o nic) will be distri b ute d t o s u bj ects i n Gr o u ps 1 a n d 2 at Visit 3  f or t he c ollecti o n of 
1) 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 s u bse q ue nt da ys) f oll o wi n g T D V 
b o oster or pla ce b o a d mi nistrati o n, a n d 2) s olicite d s yste mic A Es f or 1 4  da ys ( da y of vacci nati o n + 
1 3  s u bse q ue nt d a ys) f oll o wi n g T D V b o oster or place b o a d mi nistrati o n. T he i n vesti gat or will assess ca usalit y of 
s olicite d s yste mic A Es t o vacci ne a d mi nistrati o n (relate d or  n ot relate d).  
(t) U ns olicite d A Es will be c ollecte d b y i nter vie w a n d rec or de d f or Gr o u ps 1 a n d 2 f or 2 8 da ys ( da y of vacci nati o n 
+ 2 7 s u bse q ue nt d a ys) f oll o wi n g T D V b o oster or place b o a d mi nistrati o n. T he i n vesti gat or will cate g orize eac h 
e ve nt b y se verit y ( mil d, m o derate or se vere) a n d will assess ca usalit y t o trial vacci ne a d mi nistrati o n (relate d or 
n ot relate d). If s olicite d l ocal (i nj ecti o n site) reacti o ns a n d s yste mic A Es c o nti n ue o n Da y 8 a n d Da y 1 5 (after 
a d mi nistrati o n of t he T D V b o oster or place b o) , res pecti vel y, rec or d t he f ull d urati o n of t he e ve nt o n t he 
“ A d verse E ve nt” e C R F.  
( u) M A A Es will be c ollecte d f or Gr o u ps 1 a n d 2 fr o m Visit 3 t hr o u g h Visit 5.  
( v) A n y S A Es a n d a n y A Es lea di n g t o s u bj ect disc o nti n uati o n or wit h dra wal will be c ollecte d f or all s u bj ects f or 
t he trial d urati o n. 
( w) At Visit 3, a 1 0 m L bl o o d sa m ple a n d 4 0 m L bl o o d sa m ple will be ta ke n fr o m all s u bj ects. F or t h ose s u bj ects 
w h o are ra n d o mize d t o Gr o u ps 1 a n d 2 at Visit 3, all bl o o d sa m ples s h o ul d be ta ke n pri or t o a d mi nistrati o n of 
t he T D V b o oster d ose or place b o. T he bl o o d sa m ples ta ke n at Visit 4 s h o ul d be ta ke n at least 2 9 da ys  
(-1,  + 7  da ys) after a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3.  
( x) O ne a d diti o nal 4 0 m L bl o o d sa m ple will be c ollecte d fr o m a s u bset of 5 0  s u bj ects ( C MI s u bset; fr o m D E N-3 0 4 
o nl y) f or e x pl orat or y i m m u n o ge nicit y a nal yses fr o m Visit 1 t hr o u g h Visit 5. A n a d diti o nal 1 0 m L bl o o d sa m ple 
will als o be c ollecte d fr o m s u bj ects i n t he C MI s u bset at Visit 4 a n d Visit 5 f or f urt her e x pl orat or y 
i m m u n o ge nicit y a nal yses. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 6 6  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
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  
Selecti o n criteria f or t he pri nci pal i n vesti gat ors ( PIs) will i ncl u de si g nifica nt k n o wle d ge of t he 
trial pr ot oc ol, t he i n vesti gati o nal v acci ne, t h eir e x pertise i n t he t hera p e utic area a n d t he c o n d u ct 
of cli nical res earc h as w ell as trial partici pati o n. Ta ke da will select o ne si g nat or y 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 esti gat 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 urat el y d es cri bes t he res ults of 
t he trial. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 6 7  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
3. 3  
List of A b bre vi ati o ns  
Ter m  
Defi niti o n  
A E  
ad verse eve nt  
B MI  
b o d y m ass in de x  
C D  
cl uster of d iffere ntiati o n 
C MI  
cell-m e diate d im m u nit y  
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 v er vir us De n g ue vir us -T etra v ale nt De n g ue  Vacci ne  
D E N V  
w il d ty pe d e n g u e v ir us 
D E N V -1, -2, -3, -4  
d e n g u e v ir us ser ot y p e 1, 2, 3, a n d 4  
D H F  
d e n g u e h e m orr ha gic fe ver 
D M C  
Data M o nit ori n g C o m mittee  
D S S  
d e n g u e sh oc k sy n dr o m e  
E  
en vel o pe  
e C R F 
electr o nic case re p ort for m  
F A S  
full anal ysis set  
F A S -B  
full anal ysis set –  after T D V b o oster a d mi nistrati o n  
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 R  
g e o m etric m ea n rati o  
G M T  
g e o m etric m ea n titer 
HI V  
h u ma n im m u n o deficie nc y v ir us 
I A 
i nteri m a nal ysis 
I B 
I n v esti gat or’s Br oc h ure 
I C F 
i nf or me d c o nse nt f or m 
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 F N-γ E LI S p ot  
interfer o n -ga m ma enz y m e -li n ke d im m u n os p ot  
I N D 
I n v esti gati o nal Ne w Dr u g 
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
interacti ve res p o nse tec h n ol o g y 
I U D 
intra uteri ne de vice  
J E 
J a pa nese ence p halitis  
L A R  
le gall y acce pta ble re pres e ntati ve  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 6 8  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Ter m  
Defi niti o n  
M 0, 6, 1 2, 1 5, 1 6 , 21  M o nt h 0, 6, 1 2, 1 5, 1 6 , 21  
M A A E  
m e dicall y atte n de d ad v erse eve nt  
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 
m icr o ne utralizati o n test 5 0 % 
N S 1  
n o n -str uct ural pr otei n 1 
P B M C  
p eri p heral b l o o d m o n o n uclear cells  
P D K  
p ri mar y d o g k i d ne y 
PI  
p ri nci pal in vesti gat or  
P M D A  
P har mace uticals a n d Me dical De vices A ge nc y of J a pa n  
P P S  
p er-p r ot oc ol anal ysis set  
P P S -B  
p er-p r ot oc ol anal ysis set –  after T D V b o oster  a d mi nistrati o n  
pr M  
p re-m e m br a ne  
P T  
Preferre d Ter m  
Q T L  
q ualit y t olera n ce li mit  
S A E  
seri o us ad vers e ev e nt  
S A F  
safet y set 
S A F -B  
safet y set –  after T D V  b o oster a d mi nistrati o n  
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 F C  
s p ot f or mi n g cells 
S O C  
S yste m Or ga n Class  
S O P  
sta n dar d o perati n g pr oce d ures 
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), t h e Ta ke d a de n g ue 
vacci ne ca n di date als o k n o w n as T A K -0 0 3, is referre d t o as T D V  
T D V -1  
de n g u e ser ot y p es 2/ 1 rec o m bi na nt strai n 
T D V -2  
de n g u e ser ot y p e 2 strai n  
T D V -3  
de n g u e ser ot y p es 2/ 3 rec o m bi na nt strai n  
T D V -4  
de n g u e 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  
Y F  
yell o w fe ver  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 6 9  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
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 g u e vir us ser ot y pe -1, -2, -3, a n d -4 ( D E N V -1, 
D E N V -2, D E N V -3, a n d D E N V -4 ). T h ese d e n g ue vir uses are tr a ns mitte d fr o m h u ma n t o h u ma n 
b y m os q uit oes ( pri maril y Ae des ae g y pti ). T he 4 de n g ue vir us es are e n d e mic i n Asia, Ce ntral a n d 
S o ut h A merica, t he Cari b bea n, t he Pacifi c Isla n ds, a n d parts of Africa. T here are a n esti mate d 
3 9 0 mil li 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 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. E ver y year, ar o u n d 
5 0 0, 0 0 0 cases of d e n g ue he m orr ha gic fe ver ( D H F) re q uire h os pitalizati o n wit h a n esti mate d 
a n n ual deat h r ate 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 [3 -6 ]. 
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 uc o p e nia, a n d occ urri n g at t he sa me l ocati o n a n d ti me 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 he 4  de 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 ot ecti o n fr o m r e-i nfecti o n b y t h e sa me ser ot y pe, b ut it d oes 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) u p o n i nfecti o n wit h o ne of t he ot her 3 de n g ue 
ser ot y p es [4 ,5 ,7 ,8 ]. 
Treat me nt of d e n g ue fe v er 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 ha gic or s h oc k cas es. A n a nti viral t hera p y f or D E N V i nfecti o n is n ot 
a vaila ble. Pre v e nti ve me as ures t hat r el y o n m os q uit o c o ntr ol a n d i n di vi d ual pr ot ecti 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 n ess. T here is 
a great u n met gl o bal p u blic healt h nee d f or a s afe a n d effecti ve vacci ne t o re d uce t he m or bi dit y 
a n d m ortalit y ass o ciate d wit h de n g u e disease. Va cci ne de vel o p me nt h as f oc use d o n tetra val e 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 [3 -9 ]. A first rec o m bi na nt de n g u e 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]) was 
a p pr o ve d i n s o me c o u ntri es i n Asia a n d Lati n A merica  i n 2 0 1 5, i n E ur o pe i n 2 0 1 8, a n d i n t he 
U nite d States  i n 2 0 1 9 [1 0 ]. I nitial fi n di n gs s h o we d t hat vacci ne efficac y was differe nt b et wee n 
ser ot y p es a n d d e pe n de d o n de n g u e pre-e x p os ure stat us [1 1 ]. F urt her a n al yses s h o we d t hat p e o ple 
w h o ha d n ot bee n i nf ecte d b y de n g u e vir us bef ore vacci nati o n ha d a hi g her ris k of getti n g se v ere 
disease if t he y w ere i nf ecte d after vacci nati o n wit h C Y D-T D V [1 2 ]. I n a re vise d Strate gi c 
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 ntries c o nsi deri n g C Y D -T D V vacci n ati o n as part of t heir d e n g ue c o ntr ol 
pr o gra m, a “ pre v acci n ati o n scree ni n g str ate 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 u e -ser o p ositi ve pers o ns are vacci nat e d. He n ce, t here is a c o nti n ue d u n met p u blic healt h 
nee d f or s afer a n d m or e efficaci o us de n g ue vacci n es.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 7 0  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
T a ke d a’s 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:  
Ta ke da’s T D V  c o nsists of 1 m olec ularl y c h aracterize d, atte n uate d de n g ue s er ot y p e 2 vir us strai n 
a n d 3 rec o m bi na nt d e n g u e 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 de n g ue  
ser ot y p es 1, 3, a n d 4. T h e de n g ue ser ot y pe 2 strai n ( T D V -2) is b ase d u p o n t he atte n uate d 
la b orat or y-d eri ve d vir us D E N V -2 vir us strai n, ori gi nall y is olate d at Ma hi d ol U ni versit y, 
Ba n g k o k, T h aila n d a n d ge nerat e d b y 5 3 serial p assa 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 3 ]. T he rec o m bi na nt, atte n u ate 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 p e 
( E), of T D V-2 wit h t he pr M a n d E ge n es fr o m 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, res p ecti vel y [1 4 ]. T h us, Ta ke da’s T D V is c o m prise d of 
4  de n g u e vir us strai ns: T D V -2 ( a m olec ularl y c h aracterize d  atte n uate d strai n ), a de n g ue 
ser ot y p es 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 gu e ser ot y pes 2/ 4 rec o m bi na nt strai n ( T D V-4).  
D ata 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 nicit y, s afet y a n d i m m u n o ge nicit y pr ofiles f or Ta ke d a’s 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. C o m plete d p h ase  2 cli nical trials ha ve e na ble d t he selecti o n of a fi nal T D V d ose (i n a 
l y o p hiliz e d f or m ulati o n) a n d a 2 -d ose v acci nati o n series a d mi nistere d 3 m o nt hs (ie, 9 0 da ys) 
a part b y s u bc uta n e o us ( S C) i njecti o n f or use i n t he o n g oi n g cli nical de vel o p me nt pr o gra m.  
Res ults fr o m t he pi v otal  D E N -3 0 1 efficac y trial s h o we d t hat t he p ri mar y en d p oi nt was met, 
de m o nstrati n g t hat T D V was efficaci o us i n pre ve nti n g de n g ue fe ver i n c hil dre n a n d a d ol esce nts 
li vi n g i n de n g ue-e n de mic c o u ntries  [1 5 ]. T D V has bee n gi ve n t o > 2 0 ,0 0 0  cli nical trial s u bjects. 
All a vaila ble data als o s h o w e d t hat TD V wa s well t olerate d wit h n o si g nifi ca nt safet y c o ncer ns 
t o date [1 6 ]. 
T he c urre nt versi o n of t h e I n vesti gat or’s Br oc h ure (I B) c o ntai ns a d diti o nal pr o d uct i nf or ma ti o n 
a n d a m ore d etaile d re vie w of pre -cli nical 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 his p hase  3 trial will ca pt ure l o n g -ter m a nti b o d y persiste nce a n d safet y d ata i n healt h y s u bjects 
i n areas n o n-e n de mic f or de n g u e w h o ha v e pre vi o usl y rec ei ve d a pri mar y T D V  vacci nati o n . It 
will t he n g o o n t o  assess t he i m m u n o ge nicit y a n d safet y of a T D V  b o oster d ose  i n t his 
p o p ulati o n . 
S u bjects pre vi o usl y e nr olle d i n t w o pare nt trials ( D E N -3 0 4 a n d D E N -3 1 5) will i nitiall y be 
i n vite d t o partici pate i n t he D E N-3 0 3 f oll o w -u p trial fr o m 2 1 m o nt hs after t he first vacci n ati o n i n 
t he pri mar y vacci nati o n s eries i n t he pare nt trials. A nti b o d y pers iste nce will be assesse d i n all 
s u bjects f or u p t o 6 3  m o nt hs after t he first v acci n ati o n i n t he pri mar y v acci nati o n series f or 
s u bjects fr o m pare nt trial D E N-3 1 5 ( Me xic o) a n d f or u p t o 3 6  m o nt hs after t he first vacci n ati o n 
i n t he pri mar y vacci nati o n series f or s u bjects fr o m pare nt trial D E N-3 0 4 ( U nite d States). T he 
i m pact of a T D V b o oster vers us place b o o n t he i m m u ne res p o nse will be assesse d at 1 m o nt h 
a n d 6 m o nt hs after b o ost er a d mi nistrati o n i n all eli gi ble s u bjects r a n d o mize d t o recei ve t h e T D V 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 7 1  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
b o oster or place b o (i n a 1: 1 rati o). Safet y assess me nts will c o nti n ue f or t he d urati o n of t he trial 
( u p t o 6 m o nt hs p ost b o oster a d mi nistrati o n). 
T he safet y a n d i m m u n o ge nicit y d ata c ollect e d i n t his trial will be of i m p orta nce n ot o nl y t o 
i n di vi d uals tra velli n g t o e n de mic re gi o ns b ut als o f or t he si g nifica nt n u m ber of resi de nts wit h n o 
pri or hist or y of de n g ue i nfecti o n w h o li ve i n e n de mic a n d se mi-e n de mic areas. T he i ntr o d ucti o n 
of a T D V  b o oster i n a n o n -e n de mic setti n g will be gi n t he ass ess me nt of w het her a b o oste r is 
li kel y t o be of b e nefit i n t his p o p ulati o n. 
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 n isati 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) , G o o d 
Cli nical Practice ( G C P) G ui deli nes , a n d a p plica bl e re g ulat or y re q uir e me nts [2 ]. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 7 2  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
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  
T he pri mar y, sec o n dar y a n d e x pl orat or y o bjecti ves of t his trial are o utli ne d bel o w. 
5. 1. 1  Pri m ar y O bjecti ves  
•  T o descri be a nti b o d y p ersiste nce f or eac h of t he 4 de n g u e ser ot y p es f or u p t o 6 3  m o nt hs after 
t he first vacci n ati o n i n t he pri mar y vacci nati o n series f or s u bjects fr o m pare nt trial D E N-3 1 5 
( Me xic o) a n d f or u p t o 3 6 m o nt hs after t he first v acci nati o n i n t he pri mar y vacci nati o n series 
f or s u bjects fr o m p are nt trial D E N-3 0 4 ( U nite d States).  
•  T o descri be t he i m pa ct of a T D V b o oster d os e vs place b o o n a nti b o d y res p o nse f or eac h of 
t he 4 de n g ue ser ot y p es at 1 m o nt h a n d 6 m o nt hs p ost a d mi nistrati o n of t he T D V b o oster or 
place b o . 
5. 1. 2  Sec o n d ar y O bjecti ves  
I m m u n o ge nicity 
A nti b o d y Persiste nce  
•  T o descri be t he o v erall tre n d i n a nti b o d y d eca y f or all 4 de n g u e ser ot y p es fr o m val ues 
o btai ne d after t he pri mar y vacci nati o n series i n t he  pare nt tri als t hr o u g h 6 3  m o nt hs after t he 
first vacci nati o n i n t he pri mar y v acci n ati o n series f or s u bjects fr o m p are nt trial D E N-3 1 5 
( Me xic o) a n d t hr o u g h 3 6 m o nt hs after t he first va cci nati o n i n t he pri mar y vacci nati o n series 
f or s u bjects fr o m p are nt trial D E N-3 0 4 ( U nite d States).  
I m pa ct of a T D V B o oster D ose 
•  T o descri be t he i m pa ct of a T D V b o oster o n a nti b o d y res p o nse f or eac h of t he 4 de n g ue 
ser ot y p es f or u p t o 6 9  m o nt hs f oll o wi n g t he first vacci nati o n i n t he pri mar y vacci nati o n 
series f or s u bjects fr o m p are nt trial D E N-3 1 5 ( Me xic o) a n d f or u p t o 4 2  m o nt hs f oll o wi n g 
t he first vacci n ati o n i n t he pri mar y vacci nati o n series f or s u bjects fr o m pare nt trial D E N-3 0 4 
( U nite d States). 
S afety  
•  T o descri be t he l o n g -ter m safet y of Ta k e da’s T D V f or u p t o 6 3  m o nt hs i n pre vi o usl y 
vacci nat e d s u bjects fr o m pare nt trial D E N-3 1 5 ( M e xic o) a n d f or u p t o 3 6 m o nt hs i n 
pre vi o usl y v acci n ate d s u bjects fr o m pare nt trial D E N-3 0 4 ( U nite d States).  
•  T o assess safet y f or 6 m o nt hs f oll o wi n g a d mi nistrati o n of t he T D V b o oster or p lace b o i n 
Gr o u ps 1 a n d 2, res pecti vel y . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 7 3  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
5. 1. 3  E x pl or at or y O bjecti ves  
A p plica ble t o s u bjects fr o m pare nt trial D E N-3 1 5 ( Me xic o o nl y):  
•  T o e val uate as pects of t h e l o n g -t er m h u m oral i m m u ne res p o nse t o Ta k e da’s T D V i n all 
s u bjects at 6 3  m o nt hs after t he first va cci na ti o n i n t he pri mar y vacci nati o n series i n t he pare nt 
trial ( D E N-3 1 5) ; t his is i ncl usi ve of, b ut n ot restri cte d t o, a n assess me nt of t he a nti-de n g ue 
N o n -Str uct ural P r otei n 1 ( N S 1) a nti b o d y res p o nse. 
A p plica ble t o s u bjects fr o m pare nt trial D E N -3 0 4 ( U nite d S tates o nl y): 
•  T o e val uate as pects of t h e l o n g -t er m h u m oral i m m u ne res p o nse t o Ta k e da’s T D V i n all 
s u bjects at 3 6 m o nt hs after t he first va cci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt 
trial (D E N -3 0 4) , a n d i n t he cell-me diat e d i m m u nit y ( C MI ) s u bset at 1 m o nt h a n d 6 m o nt hs 
p ost b o oster i n t he c urre nt trial; t his is i ncl usi ve of, b ut n ot restricte d t o, a n assess me nt of t he 
a nti-de n g ue N S 1 a nti b o d y res p o nse.  
•  T o e val uate as pects of t h e l o n g -t er m cell-me diate d i m m u ne res p o nse t o Ta ke da’s T D V u p t o  
3 6 m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt tri al 
( D E N-3 0 4) a n d at 1 m o nt h a n d 6 m o nt hs p ost b o oster i n t he c urre nt trial; t his is i ncl usi ve of, 
b ut n ot restricte d t o, t he ma g nit u de (I nterfer o n -ga m ma E nz y m e -Li n ke d I m m u n os p ot [I F N-γ 
E LI S p ot]) of t he l o n g -ter m T cell-me diate d i m m u ne res p o nse t o T D V ( C MI s u bs et o nl y) . 
5. 2  
E n d p oi nts  
N ote, f or all s u bjects Visit 1 ( Da y 1 [ M 0]) a n d Visit 2 ( Da y 3 6 0 [ M 1 2]) c orres p o n d t o 2 1  m o nt hs 
a n d 3 3 m o nt hs after t he first vacci nati o n i n t h e pri mar y v acci nati o n series i n t he pare nt trial. F or 
s u bjects fr o m pare nt trial D E N-3 1 5 ( Me xic o), Visit 3 ( Da y 1 2 6 0 [ M 4 2]), Visit 4 ( Da y 1 2 9 0 
[ M 4 3]), a n d Visit 5 ( Da y 1 4 4 0 [M 4 8 ]) i n t his trial c orres p o n d t o 6 3 m o nt hs, 6 4 m o nt hs, a n d 
6 9  m o nt hs after t he fi rst vacci nati o n i n t he pri mar y vacci nati o n series, res p ecti vel y. F or s u bj ects 
fr o m pare nt tri al D E N-3 0 4 ( U nite d States), Visit 3 ( Da y 4 5 0 [ M 1 5]), Visit 4 ( Da y 4 8 0 [ M 1 6]), 
a n d Visit 5 ( Da y 6 3 0 [ M 2 1]) i n t his trial c orres p o n d t o 3 6 m o nt hs, 3 7  m o nt hs, a n d 4 2 m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trial, res pecti vel y.  
5. 2. 1  Pri m ar y E n d p oi nts  
•  Ge o metric mea n titers ( G M Ts) of ne utralizi n g a nti b o dies ( b y micr o ne utr alizati o n test 5 0 % 
[M N T
5 0]) f or eac h of t he 4 de n g u e ser ot y p es a n d s er o p ositi vit y rates ( % of s u bjects wit h 
reci pr o cal ne utralizi n g titer ≥1 0) f or eac h of t he 4 de n g u e ser ot y p es a n d m ulti ple ( 2, 3 or 4) at 
Visit 1, Visit  2, a n d Visit 3  (pri or t o a d mi nistrati o n of t he T D V b o oster or  place b o f or 
s u bjects ra n d o mize d t o Gr o u ps 1 a n d 2, res p ecti vel y) s u m marize d f or all s u bjects, f or all 
s u bjects b y p are nt trial, a n d f or all s u bjects b y ser ostat us at baseli ne i n t he pare nt trials.  
•  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 d e n g ue ser ot y p es a n d 
ser o p ositi vit y rates ( % of s u bjects wit h reci pr o cal ne utralizi n g titer ≥1 0) f or eac h of t h e 
4  de n g u e ser ot y p es a n d m ulti ple ( 2,  3  or 4) at Visit 4 a n d Visit 5 f or s u bjects ra n d o mize d t o 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 7 4  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Gr o u ps 1 a n d 2 b y trial gr o u p, b y tri al gr o u p a n d p are nt trial, a n d b y tri al gr o u p a n d 
ser ostat us at baseli ne i n t he pare nt tri als. 
5. 2. 2  Sec o n d ar y E n d p oi nts  
I m m u n o ge nicit y E n d p oi nts: 
A nti b o dy Persiste nce  
•  Ge o metric Mea n Rati o ( G M R) of ne utralizi n g a nti b o dies f or eac h of t he 4 de n g u e ser ot y p es 
f or all s u bjects, f or all s u bjects b y p are nt trial, a n d f or all s u bjects b y ser ost at us at baseli ne i n 
t he pare nt trials f or: 
–  Visit 1 v ers us Visit 2. 
–  Da y 1 2 0 ( M o nt h 4) i n t h e pare nt tri als ( 4 m o nt hs after t he first vacci nati o n i n t he pri mar y 
vacci nati o n series i n t he par e nt trials) v ers us Visit 3 i n t he c urre nt trial . 
–  Da y 2 7 0 ( M o nt h 9) i n t h e pare nt tri als ( 9 m o nt hs after t he first vacci nati o n i n t he pri mar y 
vacci nati o n series i n t he pare nt trials) v ers us Visit 1 a n d Visit 2 i n t he c urre nt trial. 
I m p act of a T D V B o oster D ose  
•  G M R of ne utralizi n g a nti b o dies f or eac h of t he 4 d e n g u e ser ot y p es f or s u bjects ra n d o mize d 
t o Gr o u ps 1 a n d 2 b y trial gr o u p, b y trial gr o u p a n d pare nt trial, a n d b y tri al gr o u p a n d 
ser ostat us at baseli ne i n t he pare nt tri als f or:  
–  Da y 1 2 0 ( M o nt h 4) i n t h e pare nt tri als ( 4 m o nt hs after t he first vacci nati o n i n t he pri mar y 
vacci nati o n series i n t he pare nt trials) v ers us Visit 4 i n t he c urre nt trial. 
–  Visit 3 v ers us Visit 4. 
–  Visit 3  v ers us Visit 5. 
–  Visit 4 v ers us Visit 5.  
–  Da y 1 2 0 ( M o nt h 4) i n t h e pare nt tri als ( 4 m o nt hs after t he first vacci nati o n i n t he pri mar y 
vacci nati o n series i n t he pare nt trials) v ers us Visit 5 i n t he c urre nt trial. 
S afet y E n d p oi nts:  
•  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) , 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 da ys) 
f oll o wi n g a d mi nistrati o n of t he T D V b o oster or pl ace b o at Visit 3 b y trial gr o u p.  
•  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) 
f oll owi n g a d mi nistrati o n of t he T D V b o oster or pl ace b o at Visit 3  b y trial gr o u p.  
•  Perce nta ge of s u bjects wit h a n y me di call y atte n de d a d verse e ve nts ( M A A Es ) f oll o wi n g 
a d mi nistrati o n of t he T D V b o oster or place b o fr o m Visit 3  t hr o u g h Visit 5 b y trial gr o u p. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 7 5  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
•  Perce nta ge of s u bjects wit h a n y seri o us a d verse e v e nts (S A Es ) fr o m Visit 1 t hr o u g h Visit 3  
pri or t o a d mi nistrati o n of t he T D V b o oster or pl ace b o.  
•  Perce nta ge of s u bjects wit h a n y S A Es f oll o wi n g a d mi nistrati o n of t he T D V b o oster or 
place b o fr o m Visit  3 t hr o u g h Vi sit 5 b y trial gr o u p. 
5. 2. 3  E x pl or at or y E n d p oi nts  
A p plica ble t o s u bjects fr o m pare nt trial D E N -3 1 5 ( Me xic o o nl y):  
•  T he assess me nt of t he l o n g -ter m h u m oral r es p o nse t o T D V will i ncl u de, b ut is n ot restricte d 
t o, t he meas ure me nt of t h e a nti-de n g ue N S 1 a nti b o d y res p o nse b y e nz y me-li n ke d 
i m m u n os or be nt assa y (a v era ge c o nce ntrati o n [relati ve u nits/ m L] of a nti-d e n g ue N S 1 
a nti b o dies f or eac h of t he 4 de n g u e ser ot y p es) usi n g bl o o d sa m ples c ollecte d fr o m all 
s u bjects at Visit 3. A d diti o nal e x pl orat or y tec h ni q ues ma y be a d d e d as t he fiel d e v ol ves.  
A p plica ble t o s u bjects fr o m pare nt trial D E N -3 0 4 ( U nite d States o nl y):  
•  T he assess me nt of t he l o n g -ter m h u m oral r es p o nse t o T D V will i ncl u de, b ut is n ot restricte d 
t o, t he meas ure me nt of t h e a nti-de n g ue N S 1 a nti b o d y res p o nse b y e nz y me -li n ke d 
i m m u n os or be nt assa y (a v era ge c o nce ntrati o n [relati ve u nits/ m L] of a nti-d e n g ue N S 1 
a nti b o dies f or eac h of t he 4 de n g u e ser ot y p es) usi n g bl o o d sa m ples c ollecte d fr o m all 
s u bjects at Visit 3, a n d fr o m s u bjects i n t he C MI s u bset at Visit 4 a n d Visit 5. A d diti o nal 
e x pl orat or y te c h ni q ues ma y b e a d d e d as t he fi el d e v ol ves.  
•  T he assess me nt of t he l o n g -ter m cell-me di ate d res p o nse t o T D V will i ncl u de, b ut is n ot 
restricte d t o, t he fre q ue n c y ( perce nta ge of s u bjects) a n d ma g nit u de ( n u m ber of S p ot F or mi n g 
Ce lls [ S F C]/ 1 06 P B M C) of I F N -γ E LI S p ot r es p o nses t o T D V usi n g bl o o d s a m ples c ollecte d 
fr o m s u bjects i n t he C MI s u bset at Visit 1, Visit 2, Visit 3, Visit 4, a n d Visit 5. Cell ular 
i m m u ne res p o nse is defi ne d as a n I F N-γ E LI S p ot res p o nse t hat is > 3 ti mes hi g her  c o m pare d 
wit h bac k gr o u n d ( n o pe pti de) a n d ≥ 5 0 s p ots per  1 0 6 P B M C. A d diti o nal e x pl orat or y 
tec h ni q ues ma y be a d de d as t he fiel d e v ol ves ( C MI s u bs et o nl y). 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 7 6  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
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 f oll o w -u p trial t hat will e val uate t he l o n g -ter m a nti b o d y p ersiste nce a n d safet y 
of Ta ke d a’s T D V i n h ealt h y a d oles ce nts a n d a d ults i n areas n o n -e n de mic f or de n g ue, i n a d diti o n 
t o assessi n g t he i m pa ct of a b o oster d ose i n t his p o p ulati o n. S u bjects w h o pre vi o usl y recei ve d 
T D V i n t w o pare nt trials, D E N -3 0 4 a n d D E N -3 1 5, will be i n vite d t o partici pate i n t his f oll o w -u p 
trial. D E N-3 0 3 will i ncl u de u p t o 6 0 0 healt h y s u bjects a ge d ≥1 3 t o ≤6 3 years at trial e ntr y. T o 
e na ble t he assess me nt of a b o oster d ose, t he tri al will be d o u ble -bli n de d, ra n d o mize d, a n d  
place b o -c o ntr olle d fr o m Visit 3 o n war ds.  
A nti b o d y persiste nce a n d safet y will be assess e d fr o m Visit 1 t hr o u g h Visit 3 ; u p t o 6 3  m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series f or s u bjects fr o m pare nt trial 
D E N -3 1 5 ( Me xic o) a n d u p t o  3 6 m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n 
series f or s u bjects fr o m p are nt trial D E N-3 0 4 ( U nite d States). F urt her c h aracterizati o n of t he 
l o n g-ter m h u m oral a n d cell-me diate d i m m u ne res p o nses t o Ta ke da’s T D V will be u n derta ke n i n 
a s ubset of a p pr o xi matel y 5 0 v ol u nteers i de ntifie d at e nr oll me nt ( C MI s u bset: partici pati o n is o n 
a v ol u ntar y basis fr o m D E N -3 0 4 o nl y)  u p t o Visit 5 . A rete nti o n p h o ne call will be ma de 
bet wee n Visits 1 a n d 2 o n Da y  1 8 0 ( M 6) t o mai nt ai n c o ntact wit h t he s u bject/t he s u bject’s 
le gall y acce pta ble re pres e ntati ve ( L A R) bet wee n site visits a n d t o re mi n d t he s u bject/t he 
s u bject’s L A R of a n y u p c o mi n g site visits. At Visit 2 t he site will disc uss a n y i nf or m ati o n t hat is 
perti ne nt t o t he b o oster p hase of t he trial wit h t he s u bject. A sec o n d rete nti o n p h o ne call will be 
ma de t o s u bjects fr o m pare nt trial D E N -3 1 5 ( Me xic o) bet wee n Visits 2 a n d 3 o n Da y 5 4 0 ( M 1 8).  
A t Visit 3, f oll o wi n g all sc he d ule d bl o o d dra ws, all s u bjects will be scree n e d f or ‘ b o oster 
eli gi bilit y’ t o det er mi ne if t he y are eli gi ble t o g o o n t o recei ve t h e T D V b o oster i n t he b o oster 
p hase. A n y s u bject w h o fails t o meet t he criteria f or ‘ b o oster eli g i bilit y’ will e n d t he trial at 
Visit  3. All eli gi ble s u bjects will be ra n d o mize d usi n g a n i nteracti ve res p o nse tec h n ol o g y (I R T) 
at Visit 3 t o 1 of 2 trial gr o u ps ( Gr o u p 1 a n d Gr o u p 2) i n a 1: 1 rati o stratifie d b y pare nt trial a n d 
ser ostat us at baseli ne i n t he pare nt tri als. S u bjects all ocate d t o Gr o u p 1 will recei v e t he T D V 
b o oster (si n gl e d ose) a n d s u bjects all ocate d t o Gr o u p 2 will recei ve place b o. T he i m pact of t he 
T D V b o oster o n ne utr alizi n g a nti b o d y titers a n d ser o p ositi vit y rates will be assesse d at 1  m o nt h 
a n d 6 m o nt hs after a d mi nistrati o n of t he T D V b o oster or place b o. Safet y assess me nts will 
c o nti n ue f or 6 m o nt hs f oll o wi n g T D V b o oster or place b o a d mi nistrati o n f or s u bjects i n Gr o u ps 1 
a n d 2. 
I m m u n o ge nicit y e v al uati o n: 
•  Ne utralizi n g a nti b o dies ( b y M N T 5 0) will be meas ure d usi n g bl o o d s a m ples c ollecte d fr o m all 
s u bjects at Visit 1, Visit 2, a n d Visit 3, a n d at Visit 4 a n d Visit 5 f or s u bjects w h o are 
ra n d o mize d t o Gr o u ps 1 a n d 2.  
•  At Visit 3, a lar ger v ol u me of bl o o d will be c ollecte d fr o m all s u bjects t o  assess e x pl orat or y 
mar kers of t h e l o n g -ter m h u m oral i m m u ne res p o ns e t o Ta ke da’s T D V. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 7 7  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
•  A p plica ble t o s u bjects fr o m pare nt trial D E N -3 0 4 ( U nite d States o nl y): A d diti o nal bl o o d 
sa m ples will be c ollecte d fr o m s u bjects i n t he C MI s u bs et t o all o w f urt her c haract erizati o n of 
t he l o n g-ter m h u m oral a n d cell-me diate d i m m u ne res p o nse t o Ta k e da’s T D V at Visit 1, Visit 
2, a n d Visit 3, a n d i n s u bjects ra n d o mize d t o Gr o u ps 1 a n d 2 at Visit 4 a n d Visit 5.  
Safet y e val uati o n:  
•  Diar y car ds will be distri b ute d t o Gr o u ps 1 a n d 2  at Visit 3 f or t he rec or di n g 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 da ys) f oll o wi n g 
a d mi nistrati o n of t he T D V b o oster or place b o. T h ese 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 d vers e e ve nts ( A Es) f or 1 4 d a ys ( da y of vacci nati o n + 1 3 da ys) 
f oll o wi n g a d mi nistrati o n of t he T D V b o oster or pl ace b o. T h ese i ncl u de: f e v er, hea d ac h e, 
ast he nia, malaise, a n d m yal gia.  
•  U ns olicite d A Es will be c ollecte d b y i nter vie w a n d rec or de d f or 2 8 d a ys ( da y of vacci nati o n 
+ 2 7 da ys) f oll o wi n g a d mi nistrati o n of t he T D V b o oster or place b o.  
•  All S A Es a n d a n y A Es le a di n g t o s u bject disc o nti n uati o n a n d wit h dra wal will be c ollecte d 
f or t he trial d urati o n f or all s u bjects. 
•  M A A Es will b e c ollecte d, f or Gr o u ps 1 a n d 2, f oll o wi n g a d mi nistrati o n of t he T D V b o oster 
or place b o fr o m Visit 3 t hr o u g h Visit 5. M A A Es are defi ne d as A Es lea di n g t o a n 
u nsc he d ule d visit t o or b y a h ealt hcare pr ofessi o n al i ncl u di n g visits t o a n e mer ge nc y 
de part me nt, b ut n ot f ulfilli n g seri o us ness criteria.  
•  F or s u bjects i n Gr o u ps 1 a n d 2 t he fi nal safet y ass ess me nts will be perf or m e d a p pr o xi matel y 
6 m o nt hs after a d mi nistrati o n of t he T D V b o oster or place b o at Visit 5.  
Data c ollecti o n will be b y el ectr o nic Cas e Re p ort F o r m (e C R F). 
S u m mar y:  
F or s u bjects fr o m pare nt trial D E N-3 1 5 ( M e xic o), t he d urati o n of t he c urre nt trial will be 
4 2  m o nt hs f or s u bjects w h o fail t o meet t he criteria f or ‘ b o oster eli gi bilit y’ at Visit 3 (i ncl usi ve 
of 3  site visits, 3 bl o o d dra ws) a n d 4 8 m o nt hs f or all ot her s u bjects ( i ncl usi ve of 5  site visits, 
5  bl o o d dra ws). F or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States), t h e trial d urati o n will be 
1 5 m o nt hs f or s u bjects w h o fail t o meet t he criteria f or ‘ b o oster eli gi bilit y’ at Visit 3 (i ncl usi ve 
of 3 site visits, 3 bl o o d dra ws) a n d 2 1 m o nt hs f or all ot her s u bjects (i ncl usi ve of 5  site visits, 
5  bl o o d dra ws). A sc h e m atic of t he trial desi g n is i ncl u de d as Fi g ure  6 .a. A sc he d ule of trial 
pr oce d ures is pr o vi de d i n Secti o n 2. 1 . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 7 8  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Fi g ure  6 .a  
S c he m atic of Tri al Desi g n  
 
F or all s u bj ects, Visit 1 a n d Visit 2 c orres p o n d t o 2 1 m o nt hs a n d 3 3 m o nt hs after t he first vacci nati o n i n t he pri mar y 
vacci nati o n series  i n t he pare nt trial. F or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o), Visit 3, Visit 4, a n d Visit 5 
i n t his trial c orres p o n d t o 6 3 m o nt hs, 6 4 m o nt hs, a n d 6 9 m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n 
series, res pecti vel y. F or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States), Visit 3, Visit 4, a n d Visit 5 i n t his trial 
c orres p o n d t o 3 6 m o nt hs, 3 7 m o nt hs, a n d 4 2 m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series, 
res pecti vel y. 
*  D ue t o c ha n ges i n t he trial desi g n i n Me xic o (P r ot oc ol A me n d me nt 3 , date d 2 2 A u g ust  2 0 2 2 ), all s u bj ects fr o m 
pare nt trial D E N-3 1 5 will b e as ke d t o re -c o nse nt usi n g a n  u p date d i nf or me d c o nse nt f or m (I C F) or a n u p date d 
i nf or me d c o nse nt a n d pe diatric asse nt f or m, as a p plica ble, at Visit 3  bef ore a n y f urt her pr ot oc ol -directe d pr oce d ures 
are perf or me d. A n  oral s u m mar y of a n y maj or c ha n ges t hat ha ve bee n ma de t o t he st u d y will be pr o vi de d t o t he 
s u bj ect a n d s u bj ect’s L A R w h ere a p plica ble i n a d diti o n t o t he I C F/ Asse nt F or m; t his will be d oc u me nte d i n t he 
me dical c hart as part of t he re -c o nse nt p r ocess. Re-c o nse nt date s h o ul d als o be d oc u me nte d i n t he e C R F . 
6. 2  
J ustific ati o n f or Tri al Desi g n, D ose, a n d E n d p oi nts  
T he st u d y p o p ulati o n i n t his trial c o nsists of healt h y a d ol esce nts a n d a d ults i n areas n o n -e n de mic 
f or de n g ue t o p er mit t he l o n g-ter m f oll o w-u p of s afet y a n d i m m u n o ge nicit y, a n d t he assess me nt 
of a T D V b o oster i n pre vi o usl y vacci nate d s u bjects. T he trial desi g n a n d t h e c ollecti o n of 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 7 9  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
s olicite d reacti o ns, s y m pt o ms an d A Es f oll o wi n g T D V b o oster  or place b o a d mi nistrati o n are 
c o nsiste nt wit h ot her v acci ne e val u ati o n trials. As t he trial will be c o n d ucte d i n areas 
n o n -e n de mic f or de n g ue, a 6 -m o nt h f oll o w -u p peri o d after a d mi nistrati o n of t he b o oster d ose is 
c o nsi dere d a de q uat e.  
T he C MI s u bs et will be restricte d  t o s u bjects fr o m D E N-3 0 4 as t hes e trial sites are k n o w n t o 
ha ve t he i nfastr u ct ure i n place t hat is re q uir e d t o c ollect, pr ocess , st ore, a n d s hi p P B M C sa m ples 
acc or di n g t o t he Sta n dar d O perati n g Pr oce d ures ( S O P) . 
C o m plete d p hase 2 trials ha ve e n a ble d t he selecti o n of t he fi nal T D V f or m ulati o n, a d mi nistere d 
b y S C i njecti o n, t hat is use d i n t his st u d y a n d has bee n ta ke n f or war d i n Ta ke da’s pi v otal de n g u e 
pr o gra m. T he c urre nt versi o n of t he I B pr o vi des 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. 
I n or der t o mai ntai n t he d o u ble -bli n d desi g n, f oll o wi n g a d mi nistrati o n of t h e T D V b o oster t o 
Gr o u p 1 at Visit  3 , a place b o (sali ne s ol uti o n f or i njecti o n) will be a d mi nistere d t o Gr o u p 2. 
J ustificati o n of t he sa m ple siz e ( u p t o 3 0 0 s u bjects per g r o u p) is i ncl u de d i n Secti o n 1 3. 3  a n d t he 
rati o nale f or t h e pr o p ose d trial is gi ve n i n Secti o n 4. 2 . 
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 assessi n g a nti b o d y persiste nce ai ms t o 
pr o vi de data o n persiste n ce of t he i m m u ne res p o nse f or > 2. 5  years ( 2. 7 5  years f or s u bjects fr o m 
pare nt trial D E N -3 0 4 a n d 5  years f or s u bjects fr o m pare nt trial D E N-3 1 5) f oll o wi n g c o m pleti o n 
of t he pri mar y vacci nati o n series. T he ti mi n g of pri mar y a n d sec o n d ar y e n d p oi nts f oll o wi n g 
a d mi nistrati o n of t he T D V b o oster will all o w a fair c o m paris o n wit h titer val ues o btai ne d i n t he 
pare nt trials a n d pr o vi de data o n  a de q u ate ti mi n g f or b o oster a d mi nistrati o n after a 2 d ose 
sc he d ule. De n g ue ne utr alizi n g a nti b o dies ha ve ge n erall y bee n 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 a n d will be t he pri mar y varia bl e meas ure d i n t his trial. 
6. 3  
Pl a n ne d D ur a ti 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 
F or s u bjects fr o m pare nt trial D E N-3 1 5 ( M e xic o), t he d urati o n of t he c urre nt trial will be 
4 2  m o nt hs f or s u bjects w h o fail t o meet t he criteria f or ‘ b o oster eli gi bilit y’ at Visit 3 a n d 
4 8  m o nt hs f or all ot her s u bjects (i ncl usi ve of b o oster a d mi nistrati o n at Visit 3  a n d f oll o w -u p 
t hr o u g h Visit 5). F or s u bj ects fr o m pare nt trial D E N-3 0 4 ( U nite d States), t h e trial d urati o n will 
be 1 5 m o nt hs f or t h ose s u bjects w h o fail t o meet t he criteri a f or ‘ b o ost e r eli gi bilit y’ at Visit 3 a n d 
2 1 m o nt hs f or all ot her s u bjects (i ncl usi ve of b o oster a d mi nistrati o n at Visit 3 a n d f oll o w -u p 
t hr o u g h Visit 5). 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 8 0  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
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 n si 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 ha n ge i n t he k n o w n ris k/ be 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.  
•  T he Data M o nit ori n g C o m mittee ( D M C) rec o m m e n ds t hat t he trial s h o ul d be s us p e n de d or 
ter mi nate d. 
•  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 safet y.  
•  T he sp 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.  
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 o ar 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 elects t o ter mi nate or s us pe n d t he trial or t he 
partici pati o n of a n i n vesti gati o nal site, a trial -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 h e 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. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 8 1  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
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 trial e ntra nce. 
7. 1  
I ncl usi o n Criteri a 
 S u b ject eli gi bilit y at trial e ntr y is d eter 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 ≥1 3 a n d ≤6 3 years at e ntr y i nt o t he c urre nt trial.  
2.  Male or fe m ale s u bjects (irres pecti ve of ser ostat us at b aseli ne i n t he pare nt trial s) w h o 
recei v e d at least o ne d ose of Ta ke d a’s T D V i n t he pare nt trials a n d h a ve dat a fr o m at least 
o ne bl o o d dra w p ost -v acci nati o n . 
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 his trial as deter mi ne d b y me di cal 
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/t he s u bject’s L A R si g ns a n d dat es a writte n i nf or me d c o nse nt/ p e diatric asse nt 
f or m a n d a n y re q uire d pri vac y a ut h orizati o n pri or t o t he i nitiati o n of a n y tri al pr oce d ures a n d 
after t he n at ure of t he 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 me nts. 
Asse nt is o btai ne d fr o m t he s u bject w here re q uire d.  
5.  S u bjects w h o ca n c o m pl y wit h trial pr o ce d ures a n d are a v aila ble f or t he d urati o n of t he 
f oll o w-u p.  
7. 2  
E xcl usi o n C riteri 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 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 bject’s a bili t y t o p artici pate i n t he trial. 
2.  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.  
3.  S u bjects t hat, i n t he o pi ni o n of t he i n vesti gat or, are n ot me dicall y eli gi ble t o pr o vi de bl o o d 
sa m ples. 
4.  S u bjects wit h a pr ol o n ge d peri o d  of ha bitati o n ( ≥1 year) i n a de n g ue e n de mic area wit hi n t he 
2 years pri or t o Visit 1.  
5.  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 i ncl u di n g 
de n g u e ( ot her t ha n Ta k e da’s T D V) , yell o w fe v er ( Y F), Ja pa n ese e n ce p halitis (J E) vir uses or 
tic k-b or ne e n ce p h alitis.  
6.  Partici pati o n i n a n y cli nical trial is all o we d, o n c o n diti o n t hat n o i n vesti gati o nal pr o d uct is 
a d mi nistere d wit hi n 3 0 da ys pri or t o bl o o d sa m pli n g  i n t he c urre nt trial. 
7.  S u bjects wit h a n y ill ness, or a hist or y of a n y 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 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.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 8 2  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
T here ma y b e i nsta nces w he n i n di vi d uals meet all e ntr y criteria e x ce 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 x cl u de d 
me dicati o n[s] or vacci ne[s] ). U n der t hese cir c u msta nces, eli gi bilit y f or trial e nr oll me nt ma y b e 
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 v e 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  
B o oster Eli gi bilit y  
Eli gi bilit y, i ncl u di n g t est res ults, m ust be c o nfir me d pri or t o ra n d o mizati o n.  
A n y s u bject w h o meets a n y of t he f oll o wi n g criteria at Visit 3 will n ot q ualif y f or ra n d o mizati o n 
t o Gr o u p 1 or 2 t o recei v e t he T D V b o oster or place b o, res p ecti vel y: 
1.  S u bjects f or w h o m b aseli ne ser ostat us is n ot defi n e d i n t he pare nt tri als.  
2.  S u bjects wit h a k n o w n h y p erse nsiti vit y or aller g y t o a n y of t he trial vacci n e c o m p o ne n ts 
(i ncl u di n g e x ci pie nts). 
3.  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).  
4.  S u bjects wit h a n y ill ness, or a hist or y of a n y 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 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.  
5.  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 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 Visit 3; use of i n hale d, 
i ntra nasal, or t o pical c ortic oster oi ds is 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 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 Visit 3.  
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 a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3 ; c o nsi der w het her a p plica ble 
as a n e x cl usi o n criteri o n or criteri o n f or dela y.  
d)  Recei pt of i m m u n osti m ula nts wit hi n 6 0 da ys pri or t o Visit  3 . 
e)  I m m u n os 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 Visit  3 . 
f) K n o w n h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n or HI V-rel ate d disease. 
g)  He patitis C vir us i nfecti o n.  
h)  Ge netic i m m u n o deficie n c y . 
6.  A b n or malities of s ple nic or t h y mic f u ncti o n.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 8 3  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
7.  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.  
8.  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 he patic diseas e).  
9.  S u bjects wit h b o d y mass i n de x ( B MI) greater t ha n or e q ual t o 3 5 k g/ m 2 ( = wei g ht i n 
k g/[ hei g ht i n meters 2]). 
1 0.  S u bjects w h o ha ve recei v e d a n y ot her v acci n es wit hi n t he 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 T D V  b o oster or place b o a d mi nistrati o n.  
1 1.  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 2.  Fe male s u bjects w h o are pre g na nt or breastf ee di n g.  
1 3.  Fe male s u bjects of c hil d -beari n g p ote ntial  w h o are se x uall y acti ve wit h me n, 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 f or at le ast 2 m o nt hs pri or t o Visit 3.  
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 least 1 year, stat us after bilateral o o p h orect o m y, or stat us after 
h ysterect o m y.  
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. 
Barrier met h o d ( c o n d o m wit h s per mici de or dia p hra g m wit h s per mici de) e ver y 
ti me d uri n g i nterc o urse. 
III. 
I ntr a uteri ne d e vice (I U D). 
I V. 
M o n o ga m o us relati o ns hi p wit h a vasect o mize d part ner. Part ner m ust ha ve bee n 
vasect o miz e d f or at least 6  m o nt hs pri or t o Visit 3 . 
1 4.  Fe male s u bjects 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 v e met h o d” f or u p t o 6 w ee ks after a d mi nistrati o n of t he T D V  b o oster 
or place b o at Visit 3. 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 or breastfee d d u ri n g 
t his peri o d. 
1 5.  A n y p ositi ve or i n det er mi nate pre g na n c y test ( Secti o n 9. 1. 1 0 ). 
1 6.  S u bjects wit h hist or y of c urre nt or pre vi o us i nfecti o n wit h a fla vi vir us s uc h as de n g ue, Zi ka, 
Y F, J E, West Nile fe ver, tic k -b or ne e n ce p h alitis or M urra y Valle y e nce p halitis a n d s u bjects 
wit h a pr ol o n ge d peri o d  of ha bitati o n ( ≥1 year) i n a de n g ue e n de mic area d uri n g trial 
c o n d uct.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 8 4  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
T here ma y b e i nsta nces w he n s u bjects meet  all t he criteri a f or ‘b o ost er eli gi bilit y ’ e x ce 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 ur e ele vati o n or recent use of 
e x cl u de d me dicati o n[s] or vacci n e[s] ). U n der t hes e circ u msta n ces, eli gi bilit y f or t h e T D V 
b o oster/ place b o ma y b e c o nsi dere d if t he a p pr o pri ate wi n d o w f or dela y has passe d, if ‘b o oster 
eli gi bilit y’ h a s bee n rec h ec ke d, a n d if t he s u bject is c o nfir me d t o be eli gi ble.  
7. 4  
Criteri a f or D el a y of Tri al V acci ne or Pl ace b o A d mi nistr ati o n or Bl o o d S a m pli n g  
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 bl o o d 
sa m pli n g or t he a d mi nistrati o n of trial vacci ne ( T D V b o oster/place b o ). T h ese sit uati o ns are liste d 
bel o w. I n t he e v e nt t hat a s u bject meets a criteri o n f or dela y e d bl o o d sa m ple  c ollecti o n or trial 
vacci ne ( T D V b o oster /place b o ) a d mi nistrati o n, t he s u bject ma y ha v e bl o o d dra w n or recei ve t he 
trial vacci ne ( T D V b o ost er/place b o ) o nce t he wi n d o w f or dela y h as passe d as l o n g as t h e s u bject 
is ot her wise eli gi ble f or trial partici pati 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 vacci nes) or 
2 8  da ys (f or li ve v acci n es) pri or t o pla n ne d trial v acci ne ( T D V b o os ter/place b o ) 
a d mi nistrati o n or bl o o d sa m pli n g.  
•  S u bjects partici pati n g i n a n y cli nical trial w here a n ot her i n vesti gati o nal pr o d uct is 
a d mi nistere d wit hi n 3 0 da ys pri or t o a n y bl o o d sa m ple c ollecti o n.  
•  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 ned trial vacci ne 
( T D V b o oster/ pla ce b o ) a d mi nistrati o n.  T his d oes n ot a p pl y t o bl o o d sa m ple c ollecti o n.  
•  S u bjects w h o ha ve recei v e d bl o o d, bl o o d pr o d ucts a n d/ or plas ma deri v ati ves or a n y 
pare nteral i m m u n o gl o b uli n pre parati o n i n t he past 3 m o nt hs pri or t o a d mi ni strati o n of t he 
trial vacci ne (T D V  b o ost er/ place b o ). T his d oes n ot a p pl y t o bl o o d sa m ple c ollecti o n.  
•  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 he reas o n f or t heir use ( pr o p h yl a xis vers us treat me nt) m us t b e d oc u me nte d. 
T D V b o oster  or place b o 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 T D V b o oster  or 
place b o a d mi nistrati o n.  T his d oes n ot a p pl y t o bl o o d sa m ple c ollecti o n.  
7. 5  
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 circ u msta nces, a s u bject’s trial p artici pati o n ma y be t er mi nate d earl y. T his mea ns 
t hat n o f urt her trial pr o ce d ures (i ncl u di n g data c ollecti o n) will be perf or me d o n t hat s u bject 
be y o n d t h e s pecifi c date of earl y ter mi nati o n of trial partici pati o n. T he pri m ar y reas o n f or earl y 
ter mi nati o n of t he s u bject’s trial partici pati 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 d erl yi n g reas o n s h o ul d be d oc u me nte d.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 8 5  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
F or scree n fail ure s u bjects, refer t o Secti o n 9. 1. 1 1 . 
1.  A d verse E v e nt: T he s u bject has e x perie n ce d a n A E (irres pecti ve of bei n g relate d/ u n relat e d t o 
t he trial vacci n e [ T D V b o oster/place b o ] or trial -relate d pr oce d ures) t h at re q uires earl y 
ter mi nati o n beca us e 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 partici 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 t er mi nati o n 
of trial partici pati o n i n t his case will be ‘ wit h dra wal d ue t o A E’ a n d n ot ‘ wit h dra wal of 
c o nse nt’, see bel o w. A n y o n g oi n g A Es le a 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 by 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 he s u bject di d n ot ret ur n t o t he cli nic a n d at least t hree atte m pts t o 
c o ntact t he s u bject w er e 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 he 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 ha n  A E).  T he 
reas o n f or wit h dra w al, 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.  
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.  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. 6  
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  
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. 5 ), ot her 
sit uati o ns ma y a p pl y i n w hic h s u bjects ma y 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 pr ot oc ol) b ut trial vacci ne ad 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 saf et y data acc or di n g t o 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 v e nt: T he s u bject has e x perie n ce d a n A E (irres pecti ve of bei n g relate d/ u nrelat e d t o 
t he trial vacci n e or trial-relate d pr oce d ures) 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 safet y, or a s u bset of ot her trial pr o ce d ures.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 8 6  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
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 he 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 ha n A E). T he 
reas o n f or wit h dra w al, 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.  
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 d eat 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 he 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 (see Secti o n 7. 5 ). 
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 trial vacci ne a d mi nistrati o ns. Pre g n a nt 
s u bjects s h o ul d, h o we 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 data 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 u l d mai ntai n c o ntact wit h 
t he pre g na nt s u bje ct a n d c o m plete a “ Cli nical Tri al Pre g na n c y F or m” as s o o n as p ossi ble. 
T he s u bject s h o ul d be f oll o we d -u p u ntil t he birt h of t he c hil d, or s p o nta ne o us or v ol u ntar y 
ter mi nati o n; w he n pre g n a nc y o utc o me i nf or mati o n bec o mes a v aila ble, t he i nf or mati o n 
s h o ul d be ca pt ure d usi n g t he sa me f or m. Data o btai ne d fr o m t he “ Cli nical Trial Pre g na nc y 
F or m” will be ca pt ure d i n t he safet y dat a 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). 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 8 7  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
8. 0  
C LI N I 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 trial vacci n es, place b o, a n d materials pr o vi de d 
directl y b y t h e s p o ns or, a n d/ or s o urce d b y ot her mea ns, t hat are re q uire 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 na ge me nt of cli nical trial material.  
8. 1  
Tri al V acci ne, Pl ace b o  a n d M ateri als  
T he i n vesti gati o nal vacci ne is Ta ke da’s T D V , a tetra vale nt vacci ne c o m prise d of 1 m olec ularl y 
c haracteriz e d, atte n u ate d de n g u e vir us strai n ( T D V -2), a n d 3 rec o m bi na nt de n g u e vir us strai ns 
( T D V-1, T D V -3, a n d 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 os e of T D V-1, T D V -2, T D V -3, a n d T D V -4, res pecti vel y. Ta ke da’s 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 T D V dil ue nt ( 3 7 m M s o di u m c hl ori de s ol uti o n) 
pri or t o a d mi nistrati o n.  
T he place b o is n or m al sali ne f or i njecti o n ( 0. 9 % s ali ne).  
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 vac ci ne a n d place b o  ca n be f o u n d i n t he P har mac y 
M a n ual or i n t he refere nce d c o m p o u n di n g m a n ual w he n a p plica bl e. Trial vacci ne will be 
pac ka ge d t o s u p p ort e nr oll me nt a n d re place me nt of s u bjects as re q uire d.  
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 D il 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 Ta k e da’s T D V , mi xi n g of t he f o ur 
T D V vacci ne s u bsta nces, filli n g i nt o vials, a n d l y o p hilizati o n of t he 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 dar k gre y b ut yl r u b ber 
st o p per a n d fli p-off al u mi n u m/ plastic o ver seal.  
T D V dil ue nt ( 3 7 m M Na Cl 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 pre -
fille d glass s yri n ge a n d is use d t o rec onstit ute t he l y o p hilize d T D V t o deli ver a 0. 5 m L d ose . 
T he d oses s h o ul d be pre p are d at t he ti me of a d mi nistrati o n b y t he u n bli n de d p har macist ( or 
a d mi nistrat or) as per t he P har mac y Ma n u al.  
Pl ac e b o:  
N or mal sali ne f or i njecti o n ( 0. 9 % s o di u m c hl ori de s ol uti o n ) will be use d as place b o. T he pl ace b o 
is prese nte d as si n gle d os e u nits f or 0. 5 m L d osi n g. 
T he sp o ns or will s u p pl y st u d y sites wit h T D V , T D V dil ue nt , a n d place b o pac ka ge d i nt o si n gle 
d ose dis pe nsi n g cart o ns.  T he cart o ns will be la bel e d i n a n  u n bli n de d fas hi o n a n d will c o ntai n 
perti ne nt trial i nf or mati o n a n d ca uti o n state me nts i n l ocal la n g u a ges. Recei vi n g, st ora ge, 
acc o u nta bilit y, a n d dis pe nsi n g of u n bli n de d trial v acci nes s h o ul d o nl y be p erf or me d b y 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 8 8  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
u n bli n de d pers o n nel (see Secti o ns 8. 2  a n d 8. 4 ) t o e ns ure t hat t he trial bli n d is n ot br o ke n. F urt her 
details ca n be f o u n d i n t he P har mac y M a n ual.  
8. 1. 2  St or a ge  
T he trial vacci ne ( T D V/ place b o ) a n d T D V dil ue nt will be s hi p pe d as per t he P har mac y Ma n u al.  
Fr o m recei pt a n d pri or t o use, t he trial vacci ne, place b o, a n d dil ue nt m ust be st ore d as per t he 
la bel a n d P har ma c y Ma n ual. 
All cli nical trial material m ust be ke pt i n a n a p pr o priate, li mite d -access, se c ure place u ntil it is 
use d or ret ur n e d t o t he sp o ns or or desi g nee f or destr ucti o n. All sp o ns or -s u p plie d trial vacci nes 
a n d place b o m ust be st or e 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 ur e l o g of t he vacci ne st ora ge 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 sp o ns or as s o o n 
as p ossi ble a n d use of t hese vacci nes, T D V dil ue nt , a n d place b o re q uir es sp o ns or a p pr o val.  
8. 1. 3  D ose a n d Re gi me n  
T he t rial vacci ne d oses t h at will be pr o vi de d t o eac h trial gr o u p at Visit 3 are prese nt e d i n  
Ta ble  8 .a. 
T he 0. 5 m L tri al vacci ne d oses will be pre pare d a n d a d mi nistere d b y t he u n bli n de d 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 as per sp o ns or 
i nstr ucti o ns. 
T D V a n d place b o will be a d mi nistere d b y t he S C r o ute.  
T a ble  8 .a  
S p o ns or -S u p plie d V acci ne s a n d Pl ace b o  
Gr o u p  
Descri pti o n  
Ti mi n g  
Gr o u p 1  
T D V, S C  
Visit 3  (a) 
Gr o u p 2  
Place b o, S C  
Visit 3  (a) 
A b bre viati o ns: M , M o nt h; S C , s u bc uta ne o us. 
(a) D a y 1 2 6 0 ( M 4 2) f or s u bj ects fr o m pare nt trial D E N-3 1 5 ( Me xic o) a n d Da y 4 5 0 ( M 1 5) f or s u bj ects fr o m pare nt 
trial D E N-3 0 4 ( U nite d States).  
8. 2  
Tri al V acci ne Assi g n me nt a n d Dis pe nsi n g Pr oce d ures  
T he vacci ne t o be use d 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 R T. Refer t o Secti o n 8. 6 . f or acc o u nta bilit y of sp o ns o r-s u p plie d vacci nes. 
T he in 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. 
T his n u m ber will be use d t hr o u g h o ut t he trial.  
T he desi g nee will use I R T a gai n at ra n d o mizati o n o n t he da y of T D V b o ost er or place b o 
a d mi nistrati o n (Visit 3) t o pr o vi de t he vacci nati o n i de ntificati o n n u m ber f or t he vacci ne d ose. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 8 9  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
T he trial vacci ne ( T D V b o oster/place b o) will be a d mi nistere d o nl y b y u n bli n de d 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 ulati o ns f or t hat s pecifi c trial. 
T he bli n de d in vesti gat or or desi g n ee will be res p o nsi ble f or o verseei n g t he a d mi nistrati o n of t he 
trial vacci ne ( T D V b oost er/ place b o ) 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.  
If sp o ns or -s u p plie d vacci ne is l ost or da ma ge d, t he site ca n re q u est a re place me nt. E x pire d 
vacci nes m ust n ot be a d mi nistere d.  
8. 2. 1  Prec a uti o ns t o B e O bser ve d W he n A d mi nisteri n g t he T D V B o oster  or Pl ace b o  
Pri or t o T D V b o oster or place b o vacci nati o n, a  s u bject m ust be deter mi ne d t o be eli gi ble a n d it 
m ust be dee me d cli nicall y a p pr o priate i n t he j u d g me nt of t he in vesti gat or t o a d mi nister t he 
b o oster d ose. Eli gi bilit y f or trial e ntr y is e val u ate d acc or di n g t o t he i ncl usi o n a n d e x cl usi o n 
criteria f or e ntr y o utli ne d i n t his pr ot oc ol ( Secti o n  7. 1  a n d Secti o n  7. 2 ). Pri or t o T D V b o oster or 
place b o a d mi nistrati o n at Visit  3 , site staff m ust deter mi ne if t he s u bject is eli gi ble t o recei ve t h e 
T D V b o oster d ose b y e val uati n g t he criteria f or ‘ b o oster eli gi bilit y’ o utli ne d i n Secti o n 7. 3 . 
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 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 p ai n at t he 
ti me of vacci nati o n s h o ul d be f oll o we d [1 7 ]. Bef ore a d mi nisteri n g t h e trial vacci ne ( T D V 
b o oster/ place b o ), t h e vacci nati o n site 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. D O N O T i nject i ntra v as c ularl y. Refer t o t he P har mac y 
M a n ual f or det ails o n pre parati o n a n d a d mi nistrati o n of trial vacci nati o n ( T D V  b o oster /place b o ). 
After a d mi nistrati o n of t he trial vacci nati o n or place b o, t he s u bject will be o bser ve d f or at least 
3 0 mi n utes f or se vere reac ti o ns. As wit h all i njecta ble vacci n es, trai ne d me dical 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 hese res c ue me dicati o ns will n ot be 
s u p plie d b y t he sp 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 he trial will be c o n d uct e d i n a d o u ble -bli n d ma n ner fr o m Visit 3 , mea ni n g t hat fr o m t his p oi nt 
o n war ds t he s u bject, t h ose res p o nsi ble  f or t he e val uati o n of a n y trial e n d p oi nt, a n d t he s p o ns or 
will all be u na ware of w h et her t he T D V b o oster or place b o was a d mi nistere d. T he 
i n vesti gati o nal va cci ne bli n d will be mai ntai ne d usi n g I R T. T he s u bjects, data c ollect ors (e g, 
in vesti gat or), a n d data e v al uat ors (e g, tri al statisticia ns) are bli n de d. O ne or m ore desi g nate d 
p har macists or vacci ne a d mi nistrat ors at t he site will be u n bli n de d. T hese u n bli n de d pers o n nel 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 9 0  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
will be res p o nsi ble f or recei vi n g a n d st ori n g t he trial vacci nes t o e ns ure t hat t he  trial bli n d is n ot 
br o ke n. T he y will als o be res p o nsi ble f or t he tri al vacci ne acc o u nta bilit y. T he u n bli n de d 
pers o n nel will ha ve n o r ole i n data c ollecti o n or e v al uati o n.  
All care m ust be ta k e n t o e ns ure t hat t he u n bli n de d re p orts a n d d o c u me nts are s hare d  o nl y wit h 
u n bli n de d pers o n nel a n d pr o perl y st ore d i n a s ec ure d area, accessi ble o nl y b y a ut h orize d 
pers o n nel.  
8. 5  
U n bli n di n g Pr oce d ure  
T he trial vacci ne bli n d, w hic h will be i n place fr o m ra n d o mizati o n at Visit 3 , s hall n ot be br o ke n 
b y t he i n vesti gat or u nl es s i nf or mati on c o ncer ni n g t he T D V b o oster  or place b o is necessar y f or 
t he me dical treat me nt of a s u bject, or i n cases of pre g na nc y if a trial s u bject re q uests it . I n t he 
e ve nt of a me di cal e mer ge nc y or pre g na n c y, if p ossi ble, t he me dical m o nit or s h o ul d be c o ntact e d 
bef ore t h e trial vacci ne bli n d is br o ke n t o disc uss t he nee d f or u n bli n di n g.  
F or u n bli n di n g a s u bject, t he trial vacci n e bli n d ca n be o btai ne d b y t he i n vesti gat or, b y accessi n g 
t he I R T. 
T he s p o ns or’s P har mac o vi gila nce De p art me nt m ust be n otifie d a s s o o n as p ossi ble if t he trial 
vacci ne bli n d is br o ke n b y t he i n vesti gat or a n d t he c o m plete d S A E or pre g n a nc y f or m, if 
a p plica ble, m ust be se nt wit hi n 2 4 h o urs. T he date, ti me, a n d reas o n t he bli n d is br o ke n m ust be 
rec or de d i n t he s o urce d o c u me nt a n d t he sa me i nf or mati o n (e x ce pt t he ti me) m ust be rec or de d o n 
t he e C R F. 
If a n y s u bject is u n bli n de d, t he s u bject m ust be wit h dra w n fr o m t he trial a n d t heir data n o l o n ger 
e val uate d. S u bjects s h o ul d c o nti n ue t o be m o nit ore d f or safet y f oll o w -u p.  
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, Pl ace b o, a n d 
O t her Cli nic al Tri al M ateri als 
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 a n d pl ace b o 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 niste re 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 us e of sp o ns or -s u p plie d trial vacci ne ( T D V/place b o ), 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 or place b o 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 ret ur n t o t h e 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 or place b o, t he i n vesti gat or or desi g n ee m ust 
verif y t he c o nt e 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 ha t t he 
q ua ntit y is c orrect, t he tri al vacci n e or place b o is 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 h as occ urre d d uri n g tr a nsit), a n d is 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, t he i n vesti gat or or desi g n ee will ac k n o wl e d ge recei pt of t he s hi p me nt 
b y rec or di n g i n t he I R T. 
If t here are a n y discre pa n cies bet wee n t he pac ki n g list a n d t he act ual pr o d u ct recei ve d, t he 
sp 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 mac 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 . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 9 1  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
T he i n vesti gat or ( or desi g nat e d i n di vi d ual) at t he site m ust mai ntai n 1 0 0 % acc o u nta bilit y f or all 
s p o ns or-s u p plie d trial vacci nes, place b o, a n d ot her cli nical trial material 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 h e trial. Acc o u nt a bilit y i ncl u des, b ut is n ot 
li mite d t o: 
•  Verif yi n g t hat t he act ual i n ve nt or y mat c hes t he 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 or place b o I D use d t o pre pare eac h 
d ose.  
•  Verif yi n g t hat 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 n cies are disc o vere d, t he s p o ns or m ust be notifie d 
i m me diatel y. 
T he i n vesti gat or ( or desi g nat e d i n di vi d ual) at eac h site m ust rec or d t he c urre nt i n ve nt or y of all 
sp o ns or -s u p plie d trial vacci nes (T D V  b o oster/ place b o ) o n a sp o ns or -a p pr o ve d trial vacci ne 
acc o u nta bilit y l o g. T h e f oll o wi n g i nf or mati o n w ill be rec or de d at a mi ni m u m: pr ot oc ol n u m ber 
a n d title, na me of in vesti gat or, site i d e ntifier a n d n u m ber, descri pti o n of sp o ns or -s u p plie d trial 
vacci nes a n d place b o, e x pir y dat e a n d a m o u nt. T h e l o g (I R T) s h o ul d i ncl u d e all re q uir e d 
i nf or mati o n as a se p arate e ntr y f or eac h s u bject t o w h o m sp o ns or -s u p plie d trial vacci n e ( T D V 
b o oster/ place b o ) is a d mi nistere d. 
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 or 
place b o, or cli nical trial materials are ret ur n e d t o  t he s p o ns or or desi g nee f or destr ucti o n, a 
re pres e ntati ve fr o m t he s p o ns or will perf or m cli ni cal trial material acc o u nt a bilit y a n d 
rec o nciliati o n. T he i n vesti gat or will r etai 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, r et 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.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 9 2  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
9. 0  
T RI A L P L A N  
N ote, f or all s u bjects Visit 1 ( Da y 1 [ M 0]) a n d Visit 2 ( Da y 3 6 0 [ M 1 2]) c orres p o n d t o 2 1  m o nt hs 
a n d 3 3 m o nt hs after t he first vacci nati o n i n t he pri mar y v acci nati o n series i n t he pare nt trial. F or 
s u bjects fr o m pare nt trial D E N-3 1 5 ( Me xic o), Visit 3 ( Da y 1 2 6 0 [ M 4 2]), Visit 4 ( Da y 1 2 9 0 
[ M 4 3]), a n d Visit 5 ( Da y 1 4 4 0 [M 4 8 ]) i n t his trial c orres p o n d t o 6 3 m o nt hs, 6 4 m o nt hs, a n d 
6 9  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series, res p ecti vel y. F or s u bj ects 
fr o m pare nt tri al D E N-3 0 4 ( U nite d S tates), Visit 3 ( Da y 4 5 0 [ M 1 5]), Visit 4 ( Da y 4 8 0 [ M 1 6]), 
a n d Visit 5 ( Da y 6 3 0 [ M 2 1]) i n t his trial c orres p o n d t o 3 6 m o nt hs, 3 7  m o nt hs, a n d 4 2 m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trial, res pecti vel y.  
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. T he 
Sc he d ule of Trial Pr oce d ures is l ocate d i n Secti o n 2. 1 . All pr oce d ures m ust be perf or me d b y 
q ualifie d a n d trai n e d staff.  
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 uir e me nts of t he i nf or me d c o ns e nt or i nf or me d c o nse nt a n d pe di atri c asse nt f or m are 
descri be d i n Secti o n 1 5. 2 . 
I nf or me d c o ns e nt or i nf or me d c o nse nt a n d pe diatric 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 -dir ecte d pr o ce d ures are perf or me d.  A d olesce nts 
w h o bec o me 1 8 years of a ge d uri n g t he c o urse of t he trial will be as ke d t o r et ur n t o t he 
i n vesti gati o nal site f or a n a d diti o nal site visit t o pr o vi de t he a p pr o pri ate writte n i nf or me d 
c o nse nt. T his s h o ul d be d o ne as s o o n as p ossi ble ( b ut n o later t ha n 2  m o nt h) after t h eir 1 8t h 
birt h da y.  
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 
i nf or me d c o nse nt a n d p e diatric asse nt is o btai ne d. If all eli gi bilit y criteri a f or e ntr y 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 bject n u m bers assi g ne d t o s u bjects w h o 
fail scree ni n g at trial e ntr y s h o ul d n ot be re use d ( S ecti o n 9. 1. 1 1 ). 
A s u bset of 5 0 v ol u nteers ( D E N -3 0 4 o nl y) will be assi g ne d t o t he C MI s u bs et at trial e ntr y t o 
per mit a m ore det aile d c h aract erizati o n of t he l o n g -ter m h u m oral a n d cell-me diate d i m m u ne 
res p o nse t o Ta k e da’s T D V u p t o Visit 5. 
D ue t o c ha n ges i n t he trial desi g n i n Me xic o ( pr ot oc ol a me n d me nt 3 , date d 2 2 A u g ust  2 0 2 2 ), all 
s u bjects fr o m pare nt trial D E N-3 1 5 ( Me xic o) will n o w be as ke d t o r e -c o nse nt usi n g an  u p date d  
i nf or me d c o nse nt f or m (I C F) or a n u p d ate d i nf or m e d c o nse nt a n d pe diatric asse nt f or m , as 
a p plica ble, at Visit 3 bef ore a n y f urt her pr ot oc ol -directe d pr o ce d ures are p erf or me d . A n  oral 
s u m mar y of a n y maj or c han ges t hat ha ve b ee n m a de t o t he st u d y will be pr o vi de d t o t he s u bject 
a n d t he s u bject’s L A R w here a p plica ble i n a d diti o n t o t he I C F/ Asse nt F or m; t his will be 
d oc u me nte d i n t he me dical c hart as p art of t he re -c o nse nt pr ocess. Re -c o nse nt date s h o ul d als o 
be d oc u me nte d i n t he e C R F.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 9 3  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
9. 1. 2  De m o gr a p hics, Me dic al Hist or y a n d Pri or Me dic ati o ns  
De m o gra p hic i nf or mati o n t o be o btai ne d at Visit 1 will i ncl u de a ge/ date of birt h, se x, race, a n d 
et h nicit y as d escri be d b y t he s u bject or s u bject’s L A R.  
A me dical hist or y u p date will be c ollecte d at e nr oll me nt ( Visit 1) a n d after ra n d o mizati o n i n 
s u bjects t hat are eli gi ble f or T D V b o oster or place b o a d mi nistrati o n at Visit 3 . T his ma y i ncl u de 
b ut is n ot li mite d t o a n y me dical hist or y t h at ma y be rele va nt t o s u bject eli gi bilit y f or trial 
partici pati o n a n d T D V b o oster or place b o a d mi nistrati o n , s uc h as pri or vacci nati o ns, 
c o nc o mita nt me dicati 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 uri es. 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 h at 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 prese 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 ncl u di n g c orres p o n di n g me dicati o n) t o be o btai ne d at Visit 1 will i ncl u d e a n y 
si g nifica nt c o n diti o ns or diseases t hat ha ve dis a p p eare d or res ol v e d at or pri or t o si g ni n g of 
i nf or me d c o nse nt or p e di atric asse nt f or m. Me dical hist or y u p date (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  pri or t o b o oster a d mi nistrati o n at Visit 3 will i ncl u de a n y si g nifi ca nt 
c o n diti o ns or diseases t hat ha ve disa p peare d or res ol ve d bet wee n Visit 1 a n d Visit 3 . A n y 
rele va nt i nf or m ati o n c ollecte d d uri n g t he pare nt trials will be access e d via t he data bas e a n d 
u p date d as necessar y t hr o u g h o ut t he t rial c o n d uct. 
A d verse me di cal oc c urre nces e mer gi n g d uri n g t h e ti me bet 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 ( T D V b o oster/place b o ) will be 
rec or de d i n t he me dical hist or y e C R F p a ge. If s uc h an a d verse me dical occ urre nce is assesse d as 
relate d t o a trial pr oce d ure t his s h o ul d be rec or de d as a n A E relate d t o st u d y pr oce d ure i n t he 
e C R F. 
All me dicati o ns, vacci nes a n d bl o o d pr o d ucts ta ke n or recei ve d b y t he s u bj ects are t o be assess e d 
a n d c ollected as Pri or or C o nc o mita nt Me dicati o ns a n d rec or de d i n t he s u bject’s s o urce 
d oc u me nt a n d e C R F as f oll o ws:  
a)  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 t he T D V b o oster or 
place b o at Visit 3  a n d u p t o 1 m o nt h ( mi ni m u m 2 8 da ys) t hereafter. 
b)  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 n y bl o o d sa m ple c ollecti o n or 
a d mi nistrati o n of t he T D V b o oster/ place b o at Visit 3  a n d u p t o 1  m o nt h ( mi ni m u m 2 8  da ys) 
t hereafter. 
c)  Bl o o d pr o d ucts a n d i m m u n o gl o b uli ns: wit hi n 3 m o nt hs pri or t o a d mi nistrati o n of t he T D V 
b o oster or place b o at Visit 3 . 
d)  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 Visit 3 . 
e)  I m m u n os u p pr essi ve t hera pies: wit hi n 6 m o nt hs pri or t o Visit 3. 
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 d oc u me nte d i n t he 
s u bject’s s o urce d oc u me nt a n d e C R F.  
F or n o n- c o m m er ci al u s e o nl y

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Tri al N o. D E N -3 0 3  
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C O N FI D E N TI A L  
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 
vacci n ati o n. Me dic ati o ns ta ke n f or tr eat 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 ( Refer t o Secti o ns 7. 2  a n d 7. 3 ): 
a)  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 i ncl u di n g 
de n g u e ( ot her t ha n Ta k e da’s T D V), Y F, J E vir uses or tic k -b or ne e nce p halitis.  
b)  A n y ot her vacci nes wit hi n t he 1 4 da ys (f or i n acti v ate d vacci nes) or 2 8 d a ys (f or li ve 
vacci nes) pri or t o a n y bl o o d sa m ple c ollecti o n or T D V  b o oster/ place b o a d mi nistrati o n at 
Visit 3.  
c)  C hr o nic use of oral ster o i 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 Visit 3; use of i n hale d, i ntra nas al, 
or t o pical c ortic oster oi ds is all o we d.  
d)  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 Visit 3.  
e)  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 
a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3 . 
f) Recei pt of i m m u n osti m ula nts wit hi n 6 0 da ys pri or t o Visit 3.  
g)  I m m u n os 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 Visit 3 . 
h)  Partici pati o n i n a n y cli nical trial w here a n ot her i n vesti gati o nal pr o d u ct is a d mi nistere d wit h i n 
3 0 da ys pri or t o a n y bl o o d sa m ple c ollecti o n . 
T hese data m ust be writte n i n t he s o urce d o c u me nts.  
9. 1. 3  D oc u me nt ati o n of Tri al E ntr a nce a n d R a n d o miz ati o n  
O nl y s u bjects w h o ha ve a si g ne d i nf or me d c o ns e nt or i nf or me d c o nse nt a n d pe diatric asse nt 
f or m, a n d meet all of t he i ncl usi o n criteria at e ntr y a n d n o ne of t he e x cl usi o n criteria at e ntr y are 
eli gi ble f or e ntr y i nt o t his trial. O nl y s u bjects w h o meet t he c riteri a f or ‘ b o oster eli gi bilit y’ at 
Visit 3  are eli gi ble f or ra n d o mizati o n i nt o t he b o oster p hase . Ra n d o mizati o n t o o ne of t w o gr o u ps 
i n a 1: 1 rati o will be stratifie d b y p are nt trial a n d s er ostat us at b aseli ne i n t h e pare nt tri als. T he 
ra n d o mizati o n sc hed ule will be creat e d a n d c o ntr olle d b y t he I R T pr o vi der usi n g t he 
ra n d o mizati o n s pecificati o n a p pr o ve d b y t he sp o ns or’s trial statisticia n, or d esi g nee.  
If t he s u bject is i neli gi ble f or ra n d o mizati o n at Visit 3, t he y will e n d t he trial at t his p oi nt a n d t he 
i n vesti gat or s h o ul d r ec or d t he pri mar y reas o n f or n o n-ra n d o mizati o n i n t he s u bject’s s o urce 
d oc u me nts a n d e C R F . 
F or n o n- c o m m er ci al u s e o nl y

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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 m will be perf or me d i n all s u bjects at Visit 1 a n d i n s u bjects ra n d o mize d t o Gr o u ps 1 
a n d 2 at Visit 3  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 ysic al 
e x a 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 me 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 n eral a p peara n ce a n d t he meas ur e me nt of wei g ht a n d hei g ht; B MI will be calc ul ate d 
a ut o maticall y. A d diti o nal p h ysical e x a mi nati o ns ma y b e 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. Cli nicall y si g nifica nt fi n di n gs 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 nt a n d e C R F. 
S u bjects ra n d o mize d t o Gr o u ps 1 a n d 2 will als o u n der g o a tar gete d s y m pt o m -directe d p h ysic al 
e x a mi nati o n at Visit 4  a n d Visit 5. A n y cli nicall y si g nifica nt c ha n ges fr o m t he baseli ne 
e x a mi nati o n perf or me d at Visit 1 s h o ul d be rec or de d i n t he s u bject’s s o urce d oc u me nts a n d 
e C R F. 
9. 1. 5  Vit al Si g ns  
V ital si g ns will be meas ure d i n all s u bjects at Visit 1, Visit 2, a n d Visit 3, a n d i n t h ose s u bjects 
ra n d o mize d t o Gr o u ps 1 a n d 2 at Visit 4 a n d Visit 5. T hese will i ncl u de ( b ut are n ot li mite d t o) 
t he meas ure m e 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 
te m perat ur e. 
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 i m m u n o ge ni cit y assess me nts will be c ollecte d fr o m all s u bjects ( 1 0 m L) at 
Visit 1, Visit 2, a n d Visit 3 , a n d fr o m t h ose s u bjects ra n d o mize d t o  Gr o u ps 1 a n d 2 at Visit 4 a n d 
Visit 5.  
A lar ger bl o o d s a m ple ( 4 0  m L) will als o be c ollecte d fr o m all s u bjects t o assess e x pl orat or y 
mar kers of t h e l o n g -ter m h u m oral i m m u ne res p o ns e t o Ta ke da’s T D V at Visit 3 pri or t o T D V 
b o oster or place b o a d mi nistrati o n f or s u bjects ra n d o mize d t o Gr o u ps 1 a n d 2.  
A p plica ble o nl y t o s u bjects fr o m pare nt trial D E N-3 0 4 (U nite d States ): A d diti o nal bl o o d sa m ples 
(4 0 -5 0 m L) will be c ollecte d fr o m s u bjects i n t he C MI s u bset t o all o w f urt her c haracterizati o n of 
t he l o n g-ter m h u m oral a n d cell -me diate d i m m u ne res p o nses t o Ta k e da’s T D V at Visit 1, Visit 2 
a n d Visit 3 , a n d i n s u bjects ra n d o mize d t o Gr o u ps 1 a n d 2 at Visit 4 a n d Visit 5.  
T he ma xi m u m v ol u me of bl o o d ta ke n at a n y si n gle visit is a p pr o xi matel y 9 0 m L f or s u bj ects i n 
t he C MI s u bset a n d a p pr o xi matel y 5 0 m L f or all ot her s u bjects. T he t otal v ol u me of bl o o d 
c ollecte d f or t he trial d ur ati o n is a p pr o xi matel y 1 9 0  t o 3 1 0 m L f or s u bjects i n t he C MI s u bset 
a n d a p pr o xi matel y 7 0  t o 9 0 m L f or all ot her s u bjects . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 9 6  of 1 3 0  
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2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Bl o o d s h o ul d be ta ke n fr o m s u bject s usi n g a n as e ptic ve ni p u nct ure tec h ni q ue f or ser ol o gi cal 
i m m u n o ge nicit y testi n g. All sa m ples m ust be c ollecte d i n acc or da nce wit h acce pta ble la b orat or y 
pr oce d ures.  
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 p r 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 nes pr o vi de d t o t he site.  
P B M Cs will be c ollecte d, pr ocesse d, la bele d a n d st ore d acc or di n g t o trial site Sta n dar d 
O perati n g Pr oce d ures ( S O P ). Refer t o t he S O P f or detaile d i nstr ucti o ns.  
9. 1. 8  S afet y Assess me nts  
Safet y assess me nts will i ncl u de t he c ollecti o n a n d rec or di n g of s olicite d l o cal (i njecti o n site) a n d 
s yste mic A Es, u ns olicite d A Es, A Es (seri o us a n d n o n-seri o us), pre g na nci es, a n d M A A Es fr o m 
Visit  3 o n war ds f or s u bj ects ra n d o mize d t o Gr o u ps 1 a n d 2 f oll o wi n g a d mi nistrati o n of t he 
b o oster d ose or place b o, res pecti vel y . 
A n y S A Es a n d a n y A Es l ea di n g t o s u bject disc o nti n uati o n a n d wit h dra wal will be c ollecte d f or 
t he e ntire trial d ur ati o n f or all s u bjects. 
Refer t o Secti o n 1 0. 1  f or safet y defi niti o ns a n d Secti o n 1 0. 4  f or details o n t he c ollecti o n a n d 
re p orti n g of A Es. 
9. 1. 9  C o ntr ace pti 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, pre g na nc y testi n g ( uri ne) will be perf or me d pri or 
t o a d mi nistrati o n of t he T D V b o oster or place b o at Visit 3 . Res ults m ust be c o nfir me d a n d 
d oc u me nte d as ne gati ve pri or t o a d mi nistrati o n of t he T D V b o oster or pl ace b o at Visit 3. 
A d diti o nal pre g n a nc y tests ma y be p erf or me d d uri n g t he trial if d ee me d necessar y b y t he 
I n v esti gat or; w here t he res ults of a uri ne pre g na n c y t est are i n d o u bt, a s er u m pre g n a nc y test will 
be perf or me d t o verif y t h e res ult.  
Fe male s u bjects of c hil d -beari n g p ote ntial w h o are se x uall y acti ve wit h me n, are a d vis e d t o use 
a n acce pta ble c o ntrace pti ve met h o d f or at least 2 m o nt hs pri or t o Visit 3. S u bjects will be 
pr o vi de d wit h i nf or mati o n o n acce pta ble met h o ds of c o ntrace pti o n as part of t he s u bject 
i nf or me d c o nse nt pr o cess a n d will be as ke d t o si g n a c o nse nt f or m at Visit 1 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 n ati o n of o va. F urt her g ui da nce 
wit h res pect t o t he a v oi d a nce of pre g n a nc y will b e pr o vi de d t o all s u bjects of c hil d beari n g 
p ote ntial at Visit 2 , a n d t o all s u bjects of c hil d beari n g p ote ntial ra n d o mize d t o Gr o u p 1 or 2 at 
Visi t 3 as part of t he trial pr oce d ures ( Secti o n 2. 1 ). Fe males of c hil d beari n g p ote ntial w h o are 
ra n d o mize d t o Gr o u p 1 or 2 a n d are se x uall y acti ve, m ust als o be re mi n de d at Visit 3  a n d at 
Visit  4 t o a d here t o acce pta ble c o ntrace pti ve met h o ds f or u p t o 6 wee ks aft er T D V b o oster or 
place b o a d mi nistrati o n; t he y will als o be a d vise d n ot t o d o nate o va or breastfee d d uri n g t his 
peri o d.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
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Acce pt a ble birt h c o nt r ol met h o ds are defi ne d as o ne or m ore of t h e f oll o wi n g: 
a)  H or m o nal c o ntrace pti ve (s uc h as or al, i njecti o n, tra ns der mal pat c h, i m pla nt, cer vical ri n g).  
b)  Barrier met h o d ( c o n d o m wit h s per mici de or dia p hra g m wit h s per mici de) e ver y ti me d uri n g 
i nterc o urse. 
c)  I U D. 
d)  M o n o ga m o us relati o ns hi p wit h a vasect o mize d part ner. Part ner m ust ha ve bee n 
vasect o miz e d f or at least 6  m o nt hs pri or t o Visit 3 . 
F or f urt her det ails refer t o Secti o n 7. 3 . 
9. 1. 1 0  Pre g n a nc y  
T o e ns ure s u bject safet y a n d t he safet y of t he u n b or n c hil d, eac h pre g n a nc y i n a s u bject ha vi n g 
recei v e d t he T D V  b o oster or place b o 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 n ce. 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 o f 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 a d mi nistrati o n of t he T D V  b o os ter or pl ace b o 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 n otificati o n f or m, t o t he c o ntact liste d i n t he 
I n v esti gat or Site File. 
S h o ul d t he pre g n a nc y occ ur aft er a d mi nistrati o n of t he bli n de d T D V  b o oster d ose or place b o, t he 
i n vesti gat or m ust i nf orm t he s u bject of t heir ri g ht t o recei v e i nf or mati o n c o ncer ni n g t he T D V  
b o oster or place b o t he y were a d mi nistere d. If t h e s u bject c h o oses t o recei v e t he u n bli n de d 
i nf or mati o n, t he i n di vi d ual bli n d s h o ul d be br o ke n b y t he i n vesti gat or a n d pr oce d ures m ust be 
f oll o we d as des cri be d i n Secti o n 8. 5 . 
9. 1. 1 1  D oc u me nt ati o n of S u bjects W h o Are  N ot  C o nsi dere d Eli gi ble f or Tri al E ntr y 
( Visit 1) or R a n d o miz ati o n ( Visit 3)  
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 n ot eli gi ble f or trial e ntr y at Visit 1  or f or ra n d o mizati o n t o 
recei v e t he T D V b o oster or place b o at Visit 3, 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 de nial of trial e ntr y (at Visit 1) is t o be rec or de d i n t he e C R F usi n g t he 
f oll o wi n g cate g ories: 
a)  Scree n fail ure ( di d n ot m eet o ne or m or e i ncl usi o n criteria at trial e ntr y or di d meet o ne or 
m ore e x cl usi o n criteria  at trial e ntr y) 
b)  Faile d t o  meet t he criteri a f or ‘ b o oster eli gi bilit y ’ ( met o ne of m ore of t he criteria f or ‘ b o oster 
eli gi bilit y’) 
F or n o n- c o m m er ci al u s e o nl y

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Tri al N o. D E N -3 0 3  
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c)  Wit h dra wal b y s u bject  
d)  Site ter mi nate d b y s p o ns or  
e)  Trial ter mi nate d b y t he s p o ns or  
f) 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 scree ni n g at a n y p oi nt s h o ul d n ot be re -us e 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 rec or ds all i njecti o ns of trial vacci ne ( T D V b o oster /place b o ) gi ve n t o t he s u bj ect 
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 Secti o n 2. 1 . 
Assess me nts s h o ul d be c o m plete d at t he desi g nate d visit(s)/ti me p oi nt(s).  
9. 3. 1  Site Visits Pri or t o T D V B o oster or Pl ace b o A d mi nistr ati o n ( Visit  1  a n d  Visit  2)  
Site visits t hat occ ur pri or t o a d mi nistrati o n of t he T D V b o oster or place b o a n d d o n ot i ncl u de a  
vacci nati o n will be perf or me d at Visit 1 a n d Visit 2.  
A d diti o nal p r oce d ures t o be perf or me d at Visit 1: 
1.  Bef ore perf or mi n g a n y trial pr oce d ure, a n I C F or i nf or me d c o ns e nt a n d pe diatric asse nt f or m 
m ust be si g ne d. Refer t o Secti o n 9. 1. 1 . 
2.  C hec k i ncl usi o n a n d e x cl usi o n criteria f or e ntr y. R efer t o Secti o ns 7. 1  a n d 7. 2 . 
3.  C ollect de m o gra p hic dat a, me dical hist or y u p date, a n d pri or me dicati o n u p d ate. Refer t o 
Secti o n 9. 1. 2 . 
4.  Perf or m a c o m plet e p h ysical e x a mi nati o n. Refer t o Secti o n 9. 1. 4 . 
Pr oce d ures t o b e perf or m e d at Visit 1 a n d Visit 2  i ncl u de: 
1.  C o nc o mita nt vacci nati o n u p date.  
2.  C hec k vital si g ns. Refer t o Secti o n 9. 1. 5 . 
3.  C ollect a n d rec or d a n y S A Es a n d a n y A Es le a di n g s u bject disc o nti n uati o n or wit h dra wal . 
Refer t o Secti o ns 1 0. 4. 4  a n d 1 0. 4. 1 . 
4.  C hec k t hat t he s u bject d o es n ot meet a n y of t he criteria f or dela y of bl o o d s a m pli n g. Refer t o 
Secti o n 7. 4 . 
5.  C ollect a bl o o d sa m ple fr o m al l s u bjects ( o ne a d diti o nal 4 0 m L bl o o d sa m ple s h o ul d be als o 
c ollecte d fr o m s u bjects i n t he C MI s u bset). Bl o o d s h o ul d be ta ke n fr o m s u bject s usi n g a n 
ase ptic ve ni p u nct ure tec h ni q ue f or ser ol o gical i m m u n o ge nicit y testi n g. Refer t o 
Secti o ns  9. 1. 6  a n d 9. 1. 7 . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
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2 2  A u g ust  2 0 2 2  
 
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9. 3. 2  Pre -V a cci n ati o n Pr oce d ures ( Visit  3 ) 
Bef ore perf or mi n g a n y f urt her pr ot oc ol -dir ecte d  pr oce d ures, all sites i n Me xic o s h o ul d c hec k 
t hat t he su bject has re -c o nse nte d usi n g t he u p date d I C F or a n u p d ate d i nf or me d c o nse nt a n d 
pe diatric asse nt f or m , as a p plica ble, c orres p o n di n g t o pr ot oc ol a m e n d me nt  3 , date d 
2 2  A u g ust  2 0 2 2 . Refer t o Secti o n 9. 1. 1  f or details. 
Pri or t o a d mi nistrati o n of t he T D V b o oster or pl ace b o at Visit 3  t he f oll o wi n g pr oce d ures will be 
u n derta ke n : 
1.  C o nc o mita nt vacci nati o n u p date.  
2.  C hec k vital si g ns. Refer t o Secti o n 9. 1. 5 . 
3.  C ollect a n d rec or d a n y S A Es a n d a n y A Es le a di n g t o s u bject disc o nti n uati o n or wit h dra wal . 
Refer t o Secti o ns 1 0. 4. 4  a n d 1 0. 4. 1 . 
4.  Perf or m pre g n a nc y testi n g i n fe m ale s u bjects of c hil d beari n g a ge. Refer t o Secti o n 9. 1. 1 0 . 
5.  Re vie w t he criteria f or ‘ b o oster eli gi bilit y ’. Refer t o Secti o n 7. 3 . 
a. A n y s u bject w h o fails t o meet t he criteri a f or ‘ b o oster eli gi bilit y’ will e n d t he trial 
f oll o wi n g bl o o d sa m ple c ollecti o n(s) at Visit 3. Refer t o Secti o n  9. 3. 7 . 
b.  S u bjects w h o meet t he criteria f or ‘ b o oster eli gi bilit y ’ will pr ocee d t o ra n d o mizati o n.  
6.  Ra n d o mizati o n. Refer t o Secti o n 9. 1. 3 . 
7.  C ollect me dical hist or y, pri or me dicati o n a n d c o n c o mita nt me dicati o ns u p date. Refer t o 
Secti o n 9. 1. 2  
8.  Perf or m a c o m plet e p h ysical e x a mi nati o n. Refer t o Secti o n 9. 1. 4 . 
9.  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 O R 
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 yste m. 
1 0.  C hec k t hat t he s u bject d o es n ot meet a n y of t he criteria f or dela y of bl o o d s a m pli n g. Refe r t o 
Secti o n 7. 4 . 
1 1.  C ollect bl o o d sa m ple s fr o m all s u bjects (o ne 1 0 m L bl o o d sa m ple a n d o n e 4 0  m L fr o m all 
s u bjects, pl us o ne a d diti o nal 4 0 m L  bl o o d s a m ple fr o m s u bjects i n t he C MI s u bset). Bl o o d 
s h o ul d be ta ke n fr o m s u bjects usi n g a n ase ptic ve ni p u nct ure tec h ni q ue f or s er ol o gi cal 
i m m u n o ge nicit y testi n g. Refer t o Secti o ns 9. 1. 6  a n d 9. 1. 7 . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 0 0  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
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C O N FI D E N TI A L  
9. 3. 3  V acci n ati o n Pr oce d ures ( Visit 3 ) 
Vacci n ati o n pr oce d ures will o nl y b e perf or me d f or s u bjects w h o meet t he criteria f or ‘b o oster 
eli gi bilit y’ ( Secti o n 7. 3 ) at Visit 3  a n d are ra n d o mize d t o Gr o u ps 1 ( T D V) a n d 2 ( place b o) : 
1.  C hec k t hat t he s u bject d o es n ot meet a n y of t he criteria f or dela y, earl y ter mi nati o n, or 
pre mat ure disc o nti n uati o n of t he trial vacci ne ( Secti o ns 7. 4 , 7. 5 , a n d 7. 6 ). 
2.  A d mi nister t he trial vacci ne ( T D V b o oster /place b o ) acc or di n g t o t he pr o ce d ures descri be d i n 
Secti o ns 8. 1. 3  a n d 8. 2 . 
9. 3. 4  P ost -V acci n ati o n Pr o ce d ures ( Visit 3 ) 
T he f oll o wi n g p ost -v acci nati o n pr oce d ures will be perf or me d at Visit 3 : 
1.  O bser vati o n f or at least 3 0 mi n utes (refer t o Secti o n 8. 2. 1 ) i ncl u di n g u ns oli cite d A Es, 
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 meas ure me nt. I nf or mati o n 
s h o ul d be rec or de d i n t he e C R F. All safet y dat a will be c ollecte d i n t he s u bj ect’s s o urce 
d oc u me nts.  
2.  Distri b uti o n of t he diar y car d.  
3.  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 t e m perat ure, 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 m ati 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 b e t he s u bject or t he  
s u bject’s L A R, b ut if a p ers o n ot her t ha n t he s u bj ect 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 p ers 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 ve trai ni n g o n t he diar y car d. 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 a n i njecti o n site A E reacti o n a n d h o w t o ta ke t heir te m perat ure, as well as h o w t o 
rec or d t h e i nf or mati o n i n t he diar y car d, s h o ul d be perf or me d w hile t he is u n der o bser vati o n 
after vacci n ati o n . 
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 uc te 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 p erf 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 ha n ge a n d be i nitia le d a n d date d. 
Please 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 yste mic A Es (i ncl u di n g b o d y te m perat ure m eas ure m e 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 
diar y car d:  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 0 1  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
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C O N FI D E N TI A L  
•  T he diar y car d s h o ul d be re vie we d wit h t he s u bject 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 at a t hat is i de ntif ie 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 tra nscri pti o n err or  s h o ul d be c orrecte d b y t he s u bject 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 ug h 
li ne a n d s h o ul d be i nitiale d a n d date d b y t h e 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 he 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 m ati o n w o ul d be 
rec or de d i n t he s u bject’s s o urce d oc u m e nt as a ver ball y re p orte d e ve nt a n d t heref ore 
ca pt ure d as a n A E a n d rec or de d i n t he A E e C R F.  
•  Starti n g o n t he da y of vacci nati o n, t he s u bject or t he s u bject’s L A R will c hec k f or 
s pecific 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 pecific ge n eralize d s y m pt o ms (s olicite d s yst e mic A Es), b o d y te m perat ure (a n y r o ute 
ma y b e use d; w here p ossi ble t he sa me r o ute s h o ul d c o nsiste ntl y be use d f or all 
te m perat ur e meas ur e me nts), a n y ot h er s y m pt o ms or c ha n ge i n t he s u bj ect’s healt 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 olicit e d A Es a n d 
b o d y te m perat ur e will be rec or de d i n t he diar y. Assess me nts s h o ul d prefera bl y ta ke pl ace 
i n t he e ve ni n g at da y’s e n d. 
•  B o d y te m perat ure me as ure me nt is t o be perf or me d usi n g t he t her m o met er pr o vi de d b y 
t he site. If t he s u bject f eels u n us uall y h ot or c ol d d uri n g t he da y, t he s u bject a n d/ or t he 
s u bject’s L A R s h o ul d c h ec k t heir te m perat ur e. If t he s u bject has a fe ver, t h e hi g h est 
b o d y te m perat ur e o bser v e d t hat da y s h o ul d be rec or de d o 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 are t o b e perf or me d usi n g 
t he r uler pr o vi de d b y t h e site. 
•  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 ure) o n t he diar y car d will c o nti n ue f or a t otal of 7 da ys a n d 
1 4  da ys, res pecti vel y, f oll o wi n g trial vacci ne ( T D V b o oster/ place b o ) a d mi nistrati o n. T he 
c ollecti o n of u ns olicite d A Es a n d me dicati o ns o n t he diar y car d  will c o nti n u e f or 2 8 da ys 
f oll o wi n g trial va cci ne (T D V b o oster/ place b o ) a d mi nistrati o n b y i nter vie w.  
4.  T he site s h o ul d sc he d ule t he ne xt trial visit ( Visit 4) wit h t he s u bject or s u bject’s L A R.  
5.  Pr o vi de fe male s u bjects of c hil d beari n g a ge wit h pre g na nc y a v oi da nce g ui da nc e a n d 
i nf or mati o n o n acce pta bl e met h o ds of c o ntrace pti o n. Refer t o Secti o ns 9. 1. 9  a n d 9. 1. 1 0 . 
6.  C ollect a n d rec or d u ns olicite d A Es. Refer t o Secti o n 1 0. 4. 1 . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 0 2  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
7.  C ollect a n d rec or d M A A Es. Refe r t o Secti o n 1 0. 4. 3 . 
8.  C ollect a n d rec or d a n y p ost -vacci nati o n S A Es. Refer t o Secti o n 1 0. 4. 4 . 
T he s u bject or t he s u bject’s L A R will recei ve a writte n re mi n der of t he ne xt pla n ne d trial acti vit y 
( Visit 4). 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 h e diar y car d da il y a n 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 diat el y ( or as s o o n as t h e 
s u bject is me dicall y sta bl e) if t he s u bject h as 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 detail s will be pr o vi de d t o t he s u bject. 
9. 3. 5  Site Visits A fter V acci n ati o n ( Visit 4 a n d Visit 5 ) 
A site visit will be perf or me d after t h e a d mi nistrati o n of t he T D V b o oster or place b o at Visit 4. 
T his visit s h o ul d occ ur at least 2 9 da ys after T D V b o oster or place b o a d mi nistrati o n. A site visit 
will als o be perf or m e d at Visit 5.  
T he f oll o wi n g pr oce d ures will be perf or me d at Visit 4:  
1.  A re vie w of t he diar y car d wit h t he s u bject or s u bject’s L A R t o:  
•  C ollect a n d rec or d s olicite d l ocal (i njecti o n site) a n d s yste mic A Es. Refer t o 
Secti o n  1 0. 4. 2 . 
•  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) a n d s yste mic A Es. 
Refer t o Secti o n 1 0. 4. 2  
•  C ollect a n d rec or d u ns olicite d A Es. Refer t o Secti o n 1 0. 4. 1 . 
•  C ollect a n d rec or d M A A Es. Refer t o Sec ti o n 1 0. 4. 3 . 
•  C ollect a n d rec or d a n y S A Es a n d a n y A Es le a di n g s u bject disc o nti n uati o n or 
wit h dra wal . Refer t o Secti o ns 1 0. 4. 4  a n d 1 0. 4. 1 . 
T he healt hcare pr ofessi o nal re vie wi n g t hes e data will disc uss t he A Es (if a n y) re p orte d b y t h e 
s u bject a n d will deter mi n e if a n y a d diti o nal dia g n oses a n d/ or A Es are prese nt a n d/ or if 
c o nc o mita nt me dicati o ns ha ve bee n use d. F or f urt her details see Se cti o n 9. 3. 4 . 
2.  U p date c o n c o mita nt me dicati o ns  a n d vacci nati o ns . Refer t o Secti o n 9. 1. 2  
3.  Perf or m a s y m pt o m -directe d p h ysi cal e xa 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 fe male s u bjects of c hil d beari n g a ge wit h pre g na nc y a v oi da nce g ui da nce a n d 
i nf or mati o n o n acce pta bl e met h o ds of c o ntrace pti o n. Refer t o Secti o ns 9. 1. 9  a n d 9. 1. 1 0 . 
6.  C hec k t hat t he s u bject d o es n ot meet a n y of t he criteria f or dela y of bl o o d s a m pli n g. Refer t o 
Secti o n 7. 4 . 
7.  C ollect a 1 0 m L bl o o d sa m ple fr o m all s u bjects ra n d o mize d t o Gr o u ps 1 a n d 2. C ollect a n 
a d diti o nal 1 0  m L bl o o d s a m ple a n d o ne 4 0 m L fr o m s u bjects i n t he C MI s u bset. Bl o o d 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 0 3  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
s h o ul d be ta ke n fr o m s u bjects u si n g a n ase ptic ve ni p u nct ure tec h ni q ue f or s er ol o gi cal 
i m m u n o ge nicit y testi n g. Refer t o Secti o ns 9. 1. 6  a n d 9. 1. 7 . 
8.  T he  site s h o ul d sc he d ule t he ne 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 ( Visit 5). 
T he s u bject or t he s u bject’s L A R will recei ve a writte n re mi n der of t he n e xt pla n ne d trial acti vit y 
( Visit 5). 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 uesti o ns a n d t o c o ntact t he site i m me diatel y ( or as s o o n as t he s u bject is me dicall y sta ble) 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 . 
T he f oll o wi n g pr oce d ures will be perf or me d at Visit 5 : 
1.  C o nc o mita nt vacci nati o n u p date.  
2.  C hec k vital si g ns. Refer t o Secti o n 9. 1. 5 . 
3.  C hec k t hat t he s u bject d o es n ot meet a n y of t he criteria f or dela y of bl o o d s a m pli n g. Refer t o 
Secti o n 7. 4 . 
4.  C ollect a 1 0 m L bl o o d sa m ple fr o m all s u bjects ra n d o mize d t o Gr o u ps 1 a n d 2. C ollect a n 
a d diti o nal 1 0  m L bl o o d s a m ple a n d o ne 4 0 m L fr o m s u bjects i n t he C MI s u bset . Bl o o d 
s h o ul d be ta ke n fr o m s u bjects usi n g a n ase ptic ve ni p u nct ure tec h ni q ue for ser ol o gi cal 
i m m u n o ge nicit y testi n g. Refer t o Secti o ns 9. 1. 6  a n d 9. 1. 7 . 
5.  Pr ocee d t o e n d of trial pr oce d ures ( Secti o n 9. 3. 7 ). 
9. 3. 6  P h o ne C o nt act –  Re mi n der C all ( D a y 1 8 0 [ M 6 ]) 
A r e mi n der p h o n e call will be perf or me d as a rete nti o n strate g y b et wee n Visit 1 a n d Visit 2 o n 
Da y 1 8 0 ( M 6) . T h e p ur p ose of t his call is t o mai ntai n c o ntact wit h t he s u bject/t he s u bject’s L A R 
a n d t o re mi n d t he s u bject/t he s u bject’s L A R a b o ut a n y u p c o mi n g site visit s. If t he s u bject/t he 
s u bject’s L A R wis hes t o descri be safet y i nf or m ati o n, t his i nf or mati o n s h o ul d o nl y be c ollecte d 
b y a tr ai ne d healt hcare pr ofessi o nal at t he site, a n d t he safet y dat a descri be d m ust be writte n 
d o w n i n s o urce d oc u m e nts. T he s u bject/t he s u bject’s L A R s h o ul d be re mi n de d t o write t he 
i nf or mati o n d o w n i n t he diar y car d a n d t o c o ntact t he site via t he tele p h o ne n u m ber pr o vi de d i n 
t he i nf or me d c o nse nt/ pe diatric asse nt f or m t o disc uss me dical q uesti o ns. A  sec o n d ret e nti o n 
p h o ne call will be ma de t o s u bjects fr o m pare nt trial D E N-3 1 5 ( M e xic o) bet wee n Visits 2 a n d 3 
o n Da y 5 4 0  ( M1 8 ). 
Tele p h o ne c o nt acts will als o be ma de f or t h ose 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 w he n a site visit ca n n ot be carrie d o ut d u e t o e x ce pti o nal circ u msta nces s uc h as  t he 
C O VI D -1 9 pa n d e mic.  
9. 3. 7  Fi n al ( E n d of Tri al) Visit  
F or s u bjects w h o fail t o meet t he criteri a f or ‘ b o oster eli gi bilit y’ at Visit 3, t he fi nal (e n d of trial) 
visit will be perf or me d at Visit  3. F or t h ose s u bjects w h o meet t he criteri a f or ‘ b o oster eli gi bilit y’ 
a n d are ra n d o mize d t o Gr o u p 1 or Gr o u p 2, t he fi n al (e n d of tria l) visit will be perf or me d at 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 0 4  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
Visit  5 . If a s u bject 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 tri al visit, if p ossi ble. F or all s u bjects recei vi n g  trial vacci ne ( T D V 
b o oster/ place b o ), t h e i n vesti gat or must c o m plete t he E n d of Trial e C R F pa ge , c hec k vital si g ns 
(refer t o Secti o n 9. 1. 5 ), c ollect a n d rec or d M A A Es (refer t o Secti o n 1 0. 4. 3 ), c ollect a n d rec or d 
a n y S A Es a n d a n y A Es l ea di n g s u bject disc o nti n u ati o n or wit h dra wal (refer t o Secti o ns 1 0. 4. 4  
a n d 1 0. 4. 1 ), a n d p erf or m a re vie w of s yste ms (a str uct ure d i nter vie w t hat q u eries t he s u bject O R 
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 yst e m). 
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 testin g will be c ollecte d as d es cri be d i n 
Secti o n  9. 1. 6 . After bl o o d dra w a n d s er u m pr ocessi n g, t he ser u m sa m ples will be preser ve d a n d 
retai ne d at a ce ntr al la b orat or y t h at was c o ntr 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 bj ects’ pers o n al i nf or mati o n t o e ns ure o pti mal c o nfi de ntia lit y a n d d efi ne d 
sta n dar d pr ocesses f or sa m ple a n d data c ollecti o n, st ora ge, a n al ysis, a n d d estr ucti o n.  
Ser u m sa m ples will be use d f or t he a nal yses 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 , b e use d t o assess, i m pr o ve or de vel o p tests rel ate d 
t o t he disease or t he i n vesti gati o nal vacci ne t hat will all o w m ore relia ble m eas ure m e nt of t he 
res p o nse t o t he i n vesti gati o nal vacci ne. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 0 5  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
1 0. 0  
A D V E R S E E V E N T S  
N ote, f or all s u bjects Visit 1 ( Da y 1 [ M 0]) a n d Visit 2 ( Da y 3 6 0 [ M 1 2] ) c orres p o n d t o 2 1 m o nt hs 
a n d 3 3 m o nt hs after t he first vacci nati o n i n t he pri mar y v acci nati o n series i n t he pare nt trial. F or 
s u bjects fr o m pare nt trial D E N-3 1 5 ( Me xic o), Visit 3 ( Da y 1 2 6 0 [ M 4 2]), Visit 4 ( Da y 1 2 9 0 
[ M 4 3]), a n d Visit 5 ( Da y 1 4 4 0 [M 4 8 ]) i n t his trial c orres p o n d t o 6 3 m o nt hs, 6 4 m o nt hs, a n d 
6 9  m o nt hs after t he first vacci nati o n i n t he pri mar y vacci nati o n series, res p ecti vel y. F or s u bj ects 
fr o m pare nt tri al D E N-3 0 4 ( U nite d States), Visit 3 ( Da y 4 5 0 [ M 1 5]), Visit 4 ( Da y 4 8 0 [ M 1 6]), 
a n d Visit 5 ( Da y 6 3 0 [ M 2 1]) i n t his trial c orres p o n d t o 3 6 m o nt hs, 3 7 m o nt hs, a n d 4 2 m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trial, res pecti vel y.  
1 0. 1  
Defi niti o ns  
1 0. 1. 1  A d verse E ve nts  
A n a d vers e e ve nt ( A E) is defi ne d as a n y u nt o wa r d me dical occ urre n ce i n a cli nical i n vesti gati o n 
s u bject a d mi nistere d a tri al vacci n e or place b o (i n cl usi ve of t he T D V b o ost er, place b o or T D V 
a d mi nistere d as part of t he pri mar y vacci nati o n series i n t he pare nt trial s); it d oes n ot necess aril y 
ha ve t o ha ve a ca usal rel ati o ns hi p wit h trial vacci ne a d mi nistrati o n.  
A n A E ca n t h eref ore b e a n y u nfa v ora bl e 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 mal la b orat or y fi n di n g), s y m pt o m, or diseas e 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 h et her or n ot it is c o nsi dere d rel ate 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 de 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 d a y  acti vities. Relie ve d 
wit h or wit h o ut s y m pt o m atic treat me nt.  
M o derate  
Gra de 2  
•  S ufficie nt disc o mf ort is prese nt t o ca us e i nterfere n ce 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 de 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 v e nts n or mal e ver y d a y acti vities. N ot relie ve d 
wit h s y m pt o matic treat m e 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] A Es) 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 t he 
trial vacci ne d os e (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 Reacti 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 or s yste mic A E o bser ve d as c o nti n ui n g o n Da y 8 a n d Da y 1 5, res pecti vel y, 
f oll o wi n g a d mi nistrati o n of t he trial vacci nati o n or place b o, will be rec or de d as a n A E o n t he 
A d verse E v e nt e C R F f or f oll o w -u p. F or t h ese persiste nt/ pr ol o n ge d s olicite d A Es t he e n d date 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 0 6  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
will be ca pt ure d o n t he A d verse E ve nt e C R F t o per mit a se parat e a nal ysis fr o m t he u ns olicite d 
A Es (see Secti o n  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 Es  
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 A Es:  
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 [1 8 ]. 
T he i nte nsit 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  
S olicite d S afet y P ar a meters  
A d verse E ve nt  
I nte nsit y G r a de  
I nte nsit y 
P ai n at i nj ecti o n site  
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 tr eat 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 (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 (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 tr eat 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  
 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 0 7  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
T a ble  1 0 .b  
S olicite d S afet y P ar a meters  (c o nti n ue d) 
A d verse E ve nt  
I nte nsit y Gr a de 
I nte nsit 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 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 [1 8 ]. 
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  
Me dicall y atte n de d A Es ( M A A E) are d efi ne d as A Es lea di n g t o a n u nsc he d ule d visit t o or b y a 
healt hcare pr ofessi o nal i ncl u di n g visits t o a n e mer ge nc y de p art me nt, b ut n ot f ulfilli n g 
seri o us ness criteria. 
1 0. 1. 5  Seri o us A d verse E ve nts ( S A Es)  
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 hr eate 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 v e nt t hat h y p ot heticall y mi g ht ha ve ca use d 
deat h if it were m ore se v ere.  
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: 
7.  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. 
8.  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 h e e ve nt is n ot i m me diatel y life t hr eate ni n g 
or fatal or d o es n ot res ult i n h os pitalizati o n.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 0 8  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
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  a n d pl ace b o  will als o be assess e 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 ne  a n d place b o , i ncl u di n g s olicite d s yste mic A Es 
(s olicite d l ocal A Es are c o nsi dere d as relate d b y d efa ult) will be ass esse 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 tri al 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 rel ati o ns hi p bet wee n t he tri al vacci ne 
a n d t he A E; t h ere 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 oce 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 h at t here is a 
reas o na bl e p ossi bilit y t h at a n e ve nt is d ue t o a trial pr oce d ure. Ot her wise, t h e relati o ns hi p s h o ul d 
be assesse d as “ N o ”.  
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 b as 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 ve 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 yse 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 ur re 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.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 0 9  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
•  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 v ers 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 g l e dia g n osis. Acc o m pa n yi n g si g ns 
(i ncl u di n g a b n or mal la b orat or y val ues) 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 priatel y as A Es.  
W orse ni n g of A Es:  
•  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 after a d mi nistrati o n of t he 
trial vacci ne or place b o , 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 ne w A E. 
I n v esti 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 h a n ge i n t he c o n diti o n 
(e g, “ w orseni 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 ter 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 …”). 
C ha n ges i n s e verit y of A Es:  
•  If t he s u bject e x perie n ces c ha n ges i n se v erit 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 p ri 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 pr o ce 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 orte 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 Es  
All A Es, w het her c o nsi dere d relate d t o t he use of t he T D V b o oster  or  pl ace b o,  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 val u es ha ve ret ur n e d t o b aseli ne, 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 1 0  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
or u ntil t here is a satisfact or y e x pla nati o n f or t he c ha n ges o bser v e 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 1, if necess ar 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 oc 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 vacci nati o n + 2 7 da ys) f oll o wi n g a d mi nistrati o n of t he 
T D V  b o oster or pla ce b o  d uri n g site visits  via i nter vie w. A Es lea di n g t o disc o nti n uati o n fr o m t he 
trial are c ollecte d t hr o u g h o ut t he trial a n d will be s u m marize d u p t o Visit 3 ( pre-v acci n ati o n) a n d 
se parat el y t h ereafter (p ost -vacci nati o n ) b y tri al gr o u p u p t o Visit 5 . 
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 mi nistrati o n of 
trial vacci ne(s) or place b o  (“rel ate d” or “ n ot relat e d”) 
•  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 
details of t he s us pecte d pr oce d ure  
•  O utc o me of e v e nt  
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 elect e d i n dicat ors of safet y will be c ollecte d o n d iar y car ds b y t he s u bjects 
f or 7 da ys (s olicite d l oc al [i njecti o n site] A Es) 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 t he T D V b o oster or place b o d os e at Visit 3  (i ncl usi ve of 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 A Es” e C R F as a p plica bl e . 
T hese will be s u m mariz e 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 site) or s yst e mic A E o bser ve d as 
c o nti n ui n g o n Da y 8 a n d Da y 1 5, res p ecti vel y, f oll o wi n g t he trial v acci n ati o n or place b o , will be 
a d diti o nall y rec or de d as a n A E o n t he A d v erse E v e 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 d ate will be ca pt ure d o n t he A d verse E ve nt e C R F t o 
per mi t a se parate 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 E 
e C R F pa ge.  
1.  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. 
                                                 
1 S A E re p orti n g will be d o ne b y e C R F. If t he e C R F s yste m is u na vaila ble, a pa per s p o ns or S A E f or m/ pa per C R F  
s h o ul d be c o m plete d a n d t he e ve nt m ust b e e ntere d i nt o t he e C R F o nce access is rest ore d.  
F or n o n- c o m m er ci al u s e o nl y

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C O N FI D E N TI A L  
2.  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 in vesti gat or.  
3.  S olicite d l ocal (i njecti o n site) reacti o ns a n d s yst e mic A Es t hat ot her wise meet t he defi niti o n 
of a n S A E (see Secti o n 1 0. 1. 2 ). 
1 0. 4. 3  C ollecti o n a n d Re p orti n g of M A A Es  
M A A Es will be c ollecte d b y cl ose m o nit ori n g of Gr o u ps 1 a n d 2, f oll o wi n g a d mi nistrati o n of t he 
T D V b o oster or place b o fr o m Visit 3 t hr o u g h Visit  5. M A A Es nee d t o be re p orte d t o t he s p o ns or 
as s o o n as p ossi ble after t he i n vesti gat or bec o mi n g a ware of t he e ve nt.  
M A A Es  m ust be rec or de d as A E s o n t he A E e C R F pa ge. M A A Es  will be s u m marize d se paratel y 
at t he e n d of t he tri al.  
1 0. 4. 4  C ollecti o n a n d Re p orti n g of S A Es  
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 e nr olle d i n t he trial  ( Visit 1). 
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  ( Visit 3 f or s u bjects w h o fail t o 
meet t he criteri a f or ‘ b o oster eli gi bilit y’ a n d Visit 5 f or all ot her s u bjects ). 
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:  
A s p o ns or S A E f or m m ust be c o m plete d, i n E n glis h, a n d si g ne d b y t h e 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 he i nf or mati 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:  
1.  A s h ort descri pti o n of t he e ve nt (i n dicati n g w het h er t he e ve nt occ urre d pre- or p ost -
vacci nat i o n) a n d t he reas o n w h y t he e ve nt is cat e g orize d as seri o us  
2.  Ca usalit y assess me nt  
3.  Pr ot oc ol n u m ber  
4.  S u bject i de ntificati o n n u m ber  
5.  I n v esti gat or’s na me 
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 f or t he atte nti o n of t h e c o ntact(s) i n t he list 
pr o vi de d t o eac h site. 
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 or 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.  
F or n o n- c o m m er ci al u s e o nl y

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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, per ma ne nt o utc o me of t h e 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 sa 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 orities  
T he s p o ns or or desi g nee will be res p o nsi ble f or t h e re p orti n g of all S us pecte 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 h er 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 ble, i n acc or da n ce wit h nati o nal re g ulati o ns i n t he c o u ntries w h ere 
t he trial is c o n d ucte d. Relati ve t o t he first a ware ness 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 hreat e ni n g 
e ve nts a n d 1 5 da ys f or ot her S U S A Rs, u nless ot her wise re q uir e d b y nati 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 her safet y iss ues w h ere t hese mi g ht materiall y 
alter t he 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 or place b o  a d mi nistrati o n or i n t he o verall c o n d uct of t he 
trial. T he i n vesti gatio 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 nce 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 onsi dere d t o b e ca use d b y t h e trial vacci ne  or place b o  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 part me nt. 
I nstr u cti 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 
File.  
F or n o n- c o m m er ci al u s e o nl y

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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 mittee  
A D M C will ha ve o versi g ht of t his cli nical 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 m ati o n is a vaila ble i n t he D M C C hart er. 
F or n o n- c o m m er ci al u s e o nl y

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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 details of pr oce d ures f or d ata ha n dli n g will be d oc u me nte d i n t he Data Ma na 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 Me 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 R Fs ( Electr o nic)  
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 ne d i nf or me d c o nse nt/  
pe diatric 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 ite ms, s uc h 
as i nc o nsiste nt dates, missi n g data, a n d q uesti o na ble val ues. Q ueries ma y b e 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 ures 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 t he c h a n ge . Reas o ns f or si g nifica nt c orrect i o ns s h o ul d a d diti o nall y b e 
i ncl 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 ness a n d acce pta bilit y at t he trial site d uri n g peri o dic visits 
b y trial m o nit ors. T he sp 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 sp 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 pri ate g o v er n me ntal h ealt 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 e x ce pti o nal circ u msta nces s uc h as  t he C O VI D-1 9 
pa n de mic,  tele p h o n e c o ntacts 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 d i x A  a n d t h ose d oc u me 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, a n d me dical rec or ds. Te m p orar y me dia s u c h as t her mal 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 date d i nf or me d c o nse nt 
or i nf or me d c o ns e nt a n d pe diatric  asse nt f or ms, s u bject a ut h orizati o n f or ms re gar di n g t he us e of 
F or n o n- c o m m er ci al u s e o nl y

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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), t he 
electr o nic c o p y of 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 nter nati o nal C o u ncil o n Har m o nisati o n (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 
esse ntial d oc u me nts s pecifie d i n I C H E 6 ( Secti o n 8) u ntil at least 2 years after t he last a p pr o v al 
of a mar k eti n g a p plicati o n f or a s pecifie d vacci ne i n dicati 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 v e d, u ntil at least 2  years after t he i n vesti gati o n is disc o nti n ue d a n d 
re 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 m e nt bet wee n t h e i n vesti gat or a n d s p o ns or  or 
desi g nee . 
Refer t o t he Cli nical St u d y Site A gree me nt f or t h e s p o ns or’s re q uir e 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 uc h d oc u m e nts.  
F or n o n- c o m m er ci al u s e o nl y

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Tri al N o. D E N -3 0 3  
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C O N FI D E N TI A L  
1 3. 0  
S T A TI S TI C A L M E T H O D S  
N ote, f or all s u bjects Visit 1 ( Da y 1 [ M 0]) a n d Visit 2 ( Da y 3 6 0 [ M 1 2]) c orres p o n d t o 2 1  m o nt hs 
a n d 3 3 m o nt hs after t he first vacci nati o n i n t he pri mar y v acci nati o n series i n t he pare nt trial. F or 
s u bjects fr o m pare nt trial D E N-3 1 5 ( Me xic o), Visit 3 ( Da y 1 2 6 0 [ M 4 2]), Visit 4 ( Da y 1 2 9 0 
[ M 4 3]), a n d Visit 5 ( Da y 1 4 4 0 [M 4 8 ]) i n t his trial c orres p o n d t o 6 3 m o nt hs, 6 4 m o nt hs, a n d 
6 9  m o nt hs after t he f irst vacci nati o n i n t he pri mar y vacci nati o n series, res p ecti vel y. F or s u bj ects 
fr o m pare nt tri al D E N-3 0 4 ( U nite d States), Visit 3 ( Da y 4 5 0 [ M 1 5]), Visit 4 ( Da y 4 8 0 [ M 1 6]), 
a n d Visit 5 ( Da y 6 3 0 [ M 2 1]) i n t his trial c orres p o n d t o 3 6 m o nt hs, 3 7  m o nt hs, a n d 4 2  m o nt hs 
after t he first vacci nati o n i n t he pri mar y vacci nati o n series i n t he pare nt trial, res pecti vel y.  
1 3. 1  
St atistic al a n d A n al ytic al Pl a ns  
A statistical a nal ysis pla n ( S A P) will be pre pare d a n d fi nalize d pri or t o u n bli n di n g of s u bjects ’ 
trial ar m assi g n me nt. T his d oc u me nt will pr o vi de f urt her det ails re gar di n g t he defi niti o n of 
a nal ysis v aria bles a n d a n al ysis met h o d ol o g y t o a d dress all trial o bjecti ves.  
B li n de d data re vie ws will be c o n d ucte d pri or t o t he u n bli n di n g of s u bjects ’ trial ar m assi g n me nt. 
T h ese revi e w s will assess t he acc urac y a n d c o m pl ete 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  
T he f oll o wi n g a nal ysis sets are d efi ne d f or t his trial:  
All Scree ne d: All s u bjects w h o a gree d t o p artici p ate i n t he c urre nt trial.  
All Scree ne d -B o oster:  All s u bjects w h o a gree d t o partici pate i n t he c urre nt trial a n d w h o were 
scree n e d f or ‘ b o oster eli gi bilit y’ t o det er mi ne if t h e y were  eli gi ble t o g o o n t o be ra n d o mize d t o 
Gr o u p 1 or Gr o u p 2.  
R a n d o mize d Set -B o oster:  All s u bjects ra n d o mize d at Visit 3 re gar dl ess of w het her t h e y 
recei v e d t he trial vacci nati o n i n t he c urre nt trial. S u bjects i n t his set will be s u m marize d 
acc or di n g t o r a n d o mize d treat me nt.  
S afet y Set ( S A F): All s u bjects w h o a gree d t o partici pate i n t he c urre nt trial a n d w h o recei ve d at 
least o ne d ose of Ta ke d a’s T D V i n t he pare nt trials. 
S afet y Set -B o oster ( S A F -B): All s u bjects w h o recei ve d at least o ne d os e of Ta ke d a’s T D V i n 
t he pare nt trials a n d w h o recei v e d t he T D V b o oster or place b o i n t he c urre nt trial.  
F ull A n al ysis Set ( F A S) : All s u bjects w h o recei v e d at least o ne d os e of Ta ke da’s T D V i n t he 
pare nt trials a n d f or w h o m t here is at least o ne v ali d f oll o w -u p meas ure m e nt u p t o Visit 3  f or 
i m m u n o ge nicit y assess m e nts i n t he c urre nt tri al. 
F ull A n al ysis Set -B o oster ( F A S -B):  All s u bj ects w h o recei ve d at least o ne d ose of Ta k e da’s 
T D V i n t he pare nt trials, t he T D V b o oster or pl ace b o i n t he c urre nt trial, a n d f or w h o m t here is at 
least o ne vali d f oll o w-u p meas ure me nt after a d mi nistrati o n of t he T D V b o oster or place b o at 
Visit 3 f or i m m u n o ge nicit y assess me nts i n t he c urre nt trial.  
F or n o n- c o m m er ci al u s e o nl y

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Per Pr ot oc ol Set ( P P S):  All s u bjects fr o m t he F A S w h o recei ve d t w o d oses of Ta ke da’s T D V i n 
t he pare nt trials wit h n o ne w maj or pr ot oc ol vi olati o ns pri or t o a d mi nistrati o n of t he b o oster or 
place b o at Visit 3  t hat c o ul d p ote ntiall y c o nf o u n d t he pri mar y e n d p oi nts i n t he c urre nt trial.  
Per Pr ot oc ol Set -B o ost er ( P P S -B):  All s u bjects fr o m t he F A S -B w h o recei ve d t w o d oses of 
Ta ke da’s T D V i n t he pare nt trials wit h n o ne w maj or pr ot oc ol vi olati o ns after a d mi nistrati o n o f 
t he T D V b o oster or pl ace b o at Visit 3 t hat c o ul d p ote ntiall y c o nf o u n d t h e pri mar y e n d p oi nts i n 
t he c urre nt trial. 
T he maj or pr ot oc ol vi olati o n criteri o n will be defi ne d as part of a data re vi e w pri or t o a n al ysis. 
T he cate g ories of n e w m aj or pr ot oc ol vi ol ati o ns i ncl u de: ( 1) n ot meeti n g s electe d e ntr y criteria, 
( 2) recei vi n g t he wr o n g trial vacci n ati o n at Visit 3 (s u bjects ra n d o mize d t o Gr o u ps 1 a n d 2 o nl y), 
( 3) recei vi n g pr o hi bite d vacci nati o ns or t hera pies (s u bjects ra n d o mize d t o Gr o u ps 1 a n d 2 o nl y), 
( 4) perf or mi n g Visit 4 i na d missi bl y o utsi de t he visit wi n d o w (s u bjects ra n d o mize d t o Gr o u ps 1 
a n d 2 o nl y), a n d ( 5) ot her maj or pr ot oc ol vi olati o ns t hat ma y be i d e ntifie d d uri n g dat a re vi e ws . 
1 3. 1. 2  A n al ysis of De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics  
A ge, ge n der, race, a n d ot her b aseli ne c haracteristics (i ncl u di n g a ge at i nf or me d c o nse nt i n t he 
pare nt trial) will be s u m mariz e d descri pti vel y f or all e nr olle d s u bjects u p o n e ntr y i nt o t he c urre nt 
trial. 
1 3. 1. 3  I m m u n o ge nicit y A n al ysis  
F or t he pri mar y a n d sec o n dar y i m m u n o ge ni cit y e n d p oi nts (ie, G M Ts of ne utralizi n g a nti b o dies 
a n d ser o p ositi vit y rates f or eac h of t he 4 de n g u e s er ot y p es a n d m ulti ple [ 2, 3 or 4]), descri pti ve 
statistics a n d 9 5 % CIs will be pr o vi de d f or eac h a p plica ble visit ( Visit 1, Visit 2, Visit 3, Visit 4, 
a n d Visit 5 i n t he c urre nt trial, a n d f or Da y 1 2 0 [ M o nt h 4] a n d Da y 2 7 0 [ M o nt h 9] i n t he pare nt 
trials [ w hic h c orres p o n ds t o 4 m o nt hs a n d 9 m o nt hs after t he first vacci nati o n i n t he pri mar y 
vacci nati o n series i n t he pa re nt trials, r es pecti vel y]). 
F or t he visit c o m paris o ns G M Rs will be s u m marize d descri pti vel y, i ncl u di n g 9 5 % CIs.  
Ser o p ositi vit y is defi ne d as a reci pr ocal ne utralizi n g titer ≥1 0. Ot her i m m u n o ge ni cit y 
meas ure me nts o btai ne d at baseli ne a n d a n y p ost -v acci nati o n visits i n t he pare nt trials ma y be 
accesse d fr o m d ata bases t o c o ntri b ute t o desi g n ate d s u m maries of i m m u n o ge ni cit y e n d p oi nts 
o ver ti me f oll o wi n g v acci nati o n.  
T he pri mar y i m m u n o ge nicit y a n al ys es will be bas e d o n t he P P S/ P P S -B; se nsiti vit y a n al ys es ma y 
be  pr o vi de d bas e d o n t he F A S/ F A S -B.  
Si milar descri pti ve a nal yses as f or t he pri mar y i m m u n o ge nicit y e n d p oi nt will be pr o vi de d f or t he 
e x pl orat or y e n d p oi nts f or eac h a p plica ble ass a y at all rele va nt ti me p oi nts, base d o n t he 
P P S/ P P S -B. S u p p orti ve a nal yses b ase d o n t he F A S/ F A S -B ma y als o b e pr o vi de d f or selecte d 
e n d p oi nts.  
F urt her details o n t he statistical a nal ysis i ncl u di n g e x pl orat or y e n d p oi nts will be pr o vi de d i n t he 
S A P.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 1 8  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
1 3. 1. 4  S afet y A n al ysis  
All s u m maries of safet y data will be base d o n s u bjects i n t he S A F/ S A F -B . 
S olicite d A Es  
Prese nce a n d se verit y ( Gra de) of s olicite d l ocal r eacti o ns (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) a n d s olicite d s yste mic A Es (fe v er, ast he nia, malaise, 
hea dac he a n d m yal gia) will be c ollecte d b y diar y car d f or 7 d a ys a n d 1 4 da ys, res pecti vel y, 
f oll o wi n g a d mi nistrati o n of t he T D V  b o oster or pl ace b o.  
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 bjects 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 f oll o wi n g 
a d mi nistrati o n of t he T D V  b o oster or place b o ( Da y 1 t hr o u g h Da y 7 f or l o cal [i njecti o n site] 
reacti o ns a n d Da y 1 t hr o u g h D a y 1 4 f or s yste mic A Es), a n d o verall. S u m maries of first o ns et of 
eac h e ve nt a n d t he n u m b er of da ys s u bjects re p orte d e x perie nci n g eac h e v e nt will als o be 
pr o vi 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 m a xi m u m se verit y will be 
use d f or ta b ulati o ns.  
Persiste nt/ pr ol o n ge d s oli cite d l ocal (i njecti o n site) reacti o ns or s yste mic A Es c o ntin ui n g o n 
Da y  8 a n d D a y 1 5  (after a d mi nistrati o n of t he T D V  b o oster or place b o) , res pecti vel y, will be 
assesse d se p aratel y. U nl ess ot her wise s pecifi e d t hese reacti o ns/ 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 pa rate listi n gs. 
U ns olicite d A Es  
U ns olicite d A Es will be s u m mariz e d b y trial gr o u p f or 2 8 da ys f oll o wi n g a d mi nistrati o n of t he 
T D V  b o oster or pla ce b o ( 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 
latest versi o n of 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. A Es lea di n g t o trial wit h dra wal will be s u m marize d u p t o Visit 3 
( pre-v acci n ati o n) a n d t hereaft er ( p ost -v acci n ati o n) b y trial gr o u p u p t o Visit 5.  
U ns olicite d A Es will be ta b ulat e d at e ac h of t h e f oll o wi n g le vels: o verall s u m mar y (s u bjects wit h 
at least 1 A E), a n d b y S O C a n d P T. I n a d diti o n, 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 great er t ha n a pre -d efi ne d fre q u e nc y (t he p erce nta ge wil l 
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 vacci ne ( T D V b o oster or place b o ). S u bjects r e p orti n g m ore t h a n 1 
occ urre nce f or t he t er m (l e vel) bei n g s u m marize d will be c o u nte d o nl y o n ce.  
M A A Es  
M A A Es will be c ollecte d f or s u bjects r a n d o mize d t o Gr o u p 1 a n d Gr o u p 2 a n d will be prese nt e d 
b y trial gr o u p fr o m Visit 3  t hr o u g h Visit 5. M A A Es will be c o de d usi n g M e d D R A a n d 
s u m marize d b y S O C a n d P T f or eac h trial gr o u p. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 1 9  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
S A Es  
S A Es will be c ollecte d t hr o u g h o ut t he tri al. S A Es will be c o de 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 u p t o Visit 3 ( pre -vacci nati o n ) a n d t hereafter ( p ost-v acci nati o n) b y trial gr o u p u p 
t o Visit 5. 
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 
D ue t o si g nifica nt dela ys  ( of > 2 years) t o b o oster a d mi nistrati o n f or s u bjects fr o m pare nt tri al 
D E N -3 1 5 ( Me xic o), a n i nteri m a nal ysis  (I A) of t he safet y a n d i m m u n o ge ni cit y dat a c ollecte d at 
trial sites i n t he U nite d States is pla n ne d w he n all s u bjects fr o m pare nt trial D E N-3 0 4 ( U nite d 
States) ha ve c o m plet e d t heir last trial visit ( Visit 5 [ Da y 6 3 0 ( M 2 1)]).  T his I A will be perf or me d 
i n a n u n bli n de d ma n ner a n d will i ncl u de t he necessar y ste ps t o e ns ure t h at n o data base 
m o dificati o ns are ma d e after u n bli n di n g f or s u bjects at trial sites i n t he U nite d States. U n bli n di n g 
of s u bjects fr o m pare nt trial D E N-3 1 5 ( Me xic o) will occ ur after all s u bjects at trial sites i n 
Me xic o ha ve c o m plete d t heir last trial visit ( Visit 5 [ Da y 1 4 4 0 ( M 4 8 )]) a n d t he trial data base has 
bee n  l oc ke d. N o m o dificat i o ns t o t he trial are pla n ne d  base d o n t he res ults of t his  I A. A n i nteri m 
C S R of data fr o m pare nt trial D E N -3 0 4 ( U nite d St ates) will n ot be pre p are d ; all trial res ults will 
be re p ort e d i n t he fi nal C S R. M ore details re gar di n g t he I A will be  pr o vi de d i n t he  S A P.  
1 3. 3  
Deter mi n ati o n of S a m ple Size  
T his trial is desi g ne d t o b e descri pti ve a n d is n ot base d o n testi n g f or mal n ull h y p ot heses.  
T heref ore, t he s a m ple siz e was n ot deter mi ne d bas e d o n f or mal statistical p o wer calc ulati o ns.  
T he n u m ber of s u bjects is c o nsi dere d t o be s uffici e nt f or t he e v al uati o n of t he o bjecti ves of t he  
trial. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 2 0  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
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 we d. S o urce d oc 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 oc u me nts are defi ne d as ori gi nal d oc u me nts, data, a n d rec or ds. 
T he i n vesti gat or a n d i nstit uti o n g uara nt ee 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 
(c o ntract researc h or ga ni zati o n ) a n d b y t he I R B or I E C. 
All as pects of t he trial a n d its d oc u me ntati o n will be s u bject t o re vie w b y t he s p o ns or or desi g nee 
(as l o n g as bli n di n g is n ot je o par dize d), 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 ne a n d place b o  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 oc 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 parate fr o m t he i nf or me d c o nse nt/ pe diatri c asse nt f or ms), a n d re vie w of e C R Fs a n d 
ass ociate d s o urce d oc u m e nts. It is i m p orta nt t hat t he i n vesti gat or a n d ot her trial pers o n nel are 
a vaila 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 e x ce pti o nal circ u msta nces 
s uc h as 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 h es s uc h as re m ote s o urce data 
verificati o n or tel e p h o ne c o ntact ma y be us e d t o e ns ure data q ualit y a n d i nt e grit y a n d  t o mai nta i n 
s u bject safet y. Alter nati v e m o nit ori n g a p pr oac h es 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 esse ntial t o t he safet y o f 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 vesti gat 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 n e t he a p pr o priate 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 de viati o n) fr o m t he i ncl us i 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 di n 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 U nite d Ki n g d o m [ M H R A], t he P har mace uticals a n d 
Me dical De vic es A g e n c y of J a pa n [ P M D A]). If t he trial site is c o ntacte d f or a n i ns pecti 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 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 2 1  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
g uara nte e access f or q ualit y ass ura nce a u dit ors t o all trial d oc u me nts as des cri be d i n 
Secti o n  1 4. 1 . 
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 n cl 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. Bef ore i nitiati o n of 
t he trial, Ta ke da or desi g nee will esta blis h q ualit y t olera nce li mits ( Q T L) ta ki n g i nt o 
c o nsi derati o n t he me dic al a n d statistical c haracteristics of t he varia bles a n d t he statist ical desi g n 
of t he trial. T his pr ocess will be 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. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 2 2  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
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 ucte d wit h t he hi g h est res pect f or t he trial s u bjects acc or di n g t o t he 
pr ot oc ol, t he et hical pri n ci ples t hat ha ve t heir ori gi n i n t he Declarati o n of  Helsi n ki [1 ], a n d t he 
I C H Har m o nize d Tri partite G ui deli ne f or G C P [2 ]. Eac h i n vesti gat or will c o nd uct t he trial 
acc or di n g t o a p plic a ble l ocal or re gi o nal re g ulat or y re q uire me 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 bilities of t he I n vesti gat or ” t hat are liste d i n  A p pe n d i 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 ni n g 
re q uire 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 pen 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 stat e, fe d eral, a n d l ocal 
re q uire 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 oc 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 dir ect 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 h ose U S sites u n willi n g t o pr o vi de na mes a n d 
titles of all me m bers d ue t o pri vac y a n d c o nflict of i nterest c o ncer ns s h o ul d i nstea d pr o vi de a 
Fe deral Wi de Ass ura n ce N u m ber or c o m p ara ble n u m ber assi g ne d b y t he De part me nt of Healt h 
a n d H u ma n Ser vices.  
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 miss i 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 nse nt/ pe diatric asse nt f or m, a n d, if a p plica bl e, s u bject recr uit me nt materi als a n d/ or 
a d vertise me nts a n d ot her d oc u me nts re q uire d b y al l a p plica ble la 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 IR B or I E C f or a p pr o val. T he I R Bs or I E C s writte n a p pr o val of 
t he pr ot oc ol a n d s u bject i nf or me d c o ns e nt/ pe diatri c 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 nee bef ore c o m me n ce me nt of t he trial (ie, bef ore s hi p me nt of t he trial 
vacci ne(s) / place b o or trial s pecific scree 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 o c ol title, n u m ber, a n d v ersi o n d ate; 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/ pe diatric 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 h e site o nce t he s p o ns 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 ble, t he s p o ns or has recei ve d per miss i 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 ves n otificati o n n o pr ot oc ol acti vities, i ncl u di n g scree ni n g ma y o cc 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 nse nt/ 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, re p orts a n d u p d ates re gar di n g t he o n g oi n g re vie w of t he tri al at 
i nter vals s pecifie d b y t h e 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 hese ite ms 
m ust be pr o vi de d t o t he s p o ns or or desi g nee.  
I n ce nti ves s h oul 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. 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 2 3  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
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 D eclarati o n of Helsi n ki [1 ] a n d t he I C H G ui deli nes [2 ] f or G C P 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 ul ati o ns. T he i nf or me d c o ns 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 d escri be t he pl a n ne d a n d 
per mitte d uses, tra nsf ers, a n d discl os ures of t he s u bject’s pers o nal a n d 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 c o 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 heet f urt her e x plai n t he nat ure of t he trial, its o bjecti ves, a n d 
p ote ntial ris ks a n d be nefits, as well as t he date i nf or me d c o nse nt/ pe diatri c 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 uirem e nts of t he s u bject a n d t he fact 
t hat t he s u bject/su 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 me dical care.  
Re -c o nse nt, r e-affir mati o n of c o nse nt: T he i n vesti gat or s h o ul d  assess t he nee d t o 
re-c o ns e nt/re-affir m ati 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. 
E x a m ple: W here t he re is a li keli h o o d t hat pe diatric s u bjects reac h a d ult h o o d w hile t he trial is 
still i n pr o gress, t he c o ns e nt pr ocess has t o b e re-e val uate d. T he n ecessit y t o re -c o ns e nt or 
re-affir m has t o be d escri be d here as well as i n t he I C F.  
T he i n vesti gat or is res p o n si 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 a n d if a p plica ble, t he s u bject a ut h orizati o n f or m. T he 
i nf or me d c o nse nt/ pe diatric asse nt f or m, s u bject 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 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, s u bject 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 m ust be writte n i n a la n g ua 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 m e nts 
of t he i nf or me d c o ns e nt/ pe diatric asse nt f or m, s u bject 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) 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 ve 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 me d a p pr o priate b y 
t he I R B or I E C. I n t he e v e nt t he s u bject is n ot ca p a ble of re n deri n g a d e q uat e 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 d e 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 ul ati o ns (e g, pe diatric asse nt f or m).  
T he s u bject/t he s u bject’s L A R m ust be gi ve n a m pl e 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 het her or n ot t o (all o w t h e c hil d t o) partici pate i n t he trial. If t he 
s u bject/t he s u bject’s L A R, deter mi nes he or s he/t heir 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 a n d s u bject a ut h orizati o n for m (if a p plica ble) 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 h e s u bject/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 h eir  
le gal na mes, n ot nic k na m es, 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 
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a n d date t he i nf or me d c o nse nt/ pe diatric asse nt f or m a n d s u bject a ut h orizati o n (if a p plica ble) 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 v er, t he 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 pli ca 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, s u bject 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 will be st ore d i n t he i n vesti g at or’s site file. T he 
i n vesti gat or m ust d oc u m e 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 di cal 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 aut 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 m e d c o nse nt/ pe diatric asse nt 
f or m. T he date t h e re vise d c o nse 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 diatri c 
asse nt f or m.  
1 5. 3  
S u bject C o nfi de nti al it y 
T he s p o ns or a n d desi 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 va c 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 b e li n ke d t o 
t he s p o ns or’s cli nical trial data base or d oc u me ntati o n via a u ni q ue i de ntificati o n n u m ber. As 
per 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 h e s u bject 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 v erif 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 v esti gat or t o per mit its m o nit or or desi g n ee, 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 nated 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 d ata 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, el ectr ocar di o gra m 
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 ns occ urri n g d uri n g a s u bject’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 di cal rec or ds re q uires 
t he s pecific a ut h orizati o n of t he s u bject/s u bject’s L A R as p art of t he i nf or me d c o nse nt/ pe diatric 
asse nt f or m pr o c ess (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 ble i nf or mati o n re m o ve d (ie, s u bject na me, a d dress, a n d ot her i de ntifier fi el 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 
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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 n ical Trials. g o v a n d/ or E u dra C T, acc or di n g t o l ocal re q uire 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 Discl os ure  
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 p u blicl y 
accessi ble we bsites s uc h as Cli nical Trials. 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.  
Ta ke da cli nical trial discl os u re 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 uire me nts of all rele v a nt re 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 dl ess of o utc o me, o n p u blicl y accessi ble we bsites s uc h as Cli nical Trials. g o v a n d/ or 
E u dra C T , as r e 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 hic h t he fi nal s u bject w as 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 s to 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. 
I n li ne wit h E C Re g ulati o n N° 1 9 0 1/ 2 0 0 6 [1 9 ], t he s p o ns or will s u b mit a s u m mar y of t he res ults 
of a pe diatri c trial wit hi n 6  m o nt hs of c o m pleti o n a n d irres pecti ve of w het h er it is part of a 
Pe diatric I n vesti gati o nal Pla n (c o m plete d or n ot yet c o m plete d) or n ot, or w het her it is i nte n de d 
f or s u b missi o n later o n as part of a variati o n, e xte nsi o n or ne w sta n d-al o n e mar keti n g 
a ut h orizati o n a p plicati o n or n ot.  
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 nj ur 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 he 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 he i n v esti gat or has q u esti o ns re gar di n g t his p olic y, he 
or s he s h o ul d c o ntact 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. 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  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 ments f or P har mace uticals f or 
H u ma n Use (I C H). I C H har m o nize 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 2): 
G ui deli ne f or G o o d Cli nical Practice E 6.  
3.  G u bler DJ. E pi de mic de 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.  
4.  G uz ma n M G, 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.  
5.  W orl d Healt h Or ga niz ati o n. De n g ue a n d s e ve re d e n g u e. Fact S heet. 2 0 22 . ( A vaila ble at: 
htt p:// w w w. w h o.i nt/ me diace ntr e/fa cts heets/fs 1 1 7/ e n/) (access e d  2 9  J ul y 2 0 2 2 ). 
6.  Si m m o ns C P, Farrar JJ, N g u ye n v V, Wills B. De n g ue. N E n gl J Me d. 2 0 1 2; 3 6 6( 1 5): 1 4 2 3 -
3 2.  
7.  W orl d Healt h Or ga niz ati o n. De n g ue he 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. 1 9 9 7. ( A vai la ble at: htt ps://a p ps. w h o.i nt/iris/ ha n dle/ 1 0 6 6 5/ 4 1 9 8 8 ) 
(accesse d 2 9  J uly  2 0 2 2 ). 
8.  W orl d Healt h Or ga niz ati o n. De n g ue g ui deli nes f or dia g n osis, tr eat me nt, pr e ve nti o n a n d 
c o ntr ol: ne w e diti o n. 2 0 0 9. ( A vaila ble at: htt ps://a p ps. w h o.i nt/iris/ ha n dle/ 1 0 6 6 5/ 4 4 1 8 8 ) 
(accesse d 2 9  J ul y 2 0 2 2 ). 
9.  Halstea d S B, D ee n J. T he f ut ure of de n g ue v acci n es. La ncet. 2 0 0 2; 3 6 0( 9 3 4 1): 1 2 4 3 -5.  
1 0.  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 1.  Ha di ne g or o S R, Arre d o n d o -Garcia 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 -Ter m Safet y of a De n g ue Vacci ne i n  Re gi o ns of E n d e 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 2.  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 h a bert T, et al. Effect of 
De n g ue Ser ostat us o n D e n g ue Vacci 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 3.  Y o ksa n S, B ha mara pra vati N, Halstea d S. De n g ue vir us vacci ne de vel 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 a ssa ge d i n pri mar y ki d n e y cells. 
Ar b o vir us res earc h i n A ustralia Pr ocee di n gs of t h e 4t h S y m p osi u m. Bris ba n e, A ustralia: 
C SI R O/ QI M R; 1 9 8 6. p. 3 5 -8.  
1 4.  H ua n g C Y, B utr a pet S, Ts uc hi ya K R, B h a mara 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.  
F or n o n- c o m m er ci al u s e o nl y

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1 5.  Bis wal S, B orj a -Ta b ora C, Marti nez Var gas L, Velás q uez H, T heresa Alera M, Sierra V, 
et al; TI D E S st u d y gr o u p. Efficac y of a t etra val e nt de n g u e vacci ne i n healt h y c hil dre n a ge d 
4 -1 6 years: a ra n d o mise d, place b o -c o ntr olle d, p hase 3 trial. La ncet. 2 0 2 0 Ma y 
2; 3 9 5( 1 0 2 3 4): 1 4 2 3 -3 3.  
1 6.  Patel S S, Ra usc he r M, K u dela M, Pa n g H. Cli nical Safet y E x perie n ce of T A K-0 0 3 f or 
De n g ue Fe ver: a ne w Tetra vale nt Li ve Atte n uate d Vacci n e Ca n di date. Cli n I nfect Dis. 2 0 2 2 
Ma y 2 6:ci ac 4 1 8.  
1 7.  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 pe r - 
Se pte 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.  
1 8.  K o hl K S, Marc y S M, Bl u m M, C o n nell J o nes M, Da ga n R, Ha ns e n J, et al. Fe ver aft er 
i m m u nizati o n: c urre nt c o nce pts a n d i m pr o ve d f ut ure scie ntific u n d ersta n di n g. Cli n I nfect 
Dis. 2 0 0 4; 3 9( 3): 3 8 9 -9 4.  
1 9.  E C Re g ulati o n N° 1 9 0 1/ 2 0 0 6 O F T H E E U R O P E A N P A R LI A M E N T A N D O F T H E 
C O U N CI L of 1 2 Dece m ber 2 0 0 6 o n me dici nal pr o d ucts f or pe diatri c use a n d a me n di n g 
Re g ulati o n ( E E C) N o 1 7 6 8/ 9 2, Directi ve 2 0 0 1/ 2 0/ E C, Directi ve 2 0 0 1/ 8 3/ E C a n d Re g ulati o n 
( E C) N o 7 2 6/ 2 0 0 4. 
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A p pe n d i 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 he 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 assess me nts, are N O T perf or me d o n p ot e ntial s u bjects pri or t o t he recei pt of 
writte n a p pr o val fr o m rel e va 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 v al of t he trial a n d a n y c h a n ges b y a n a p pr o pri ate I R B/I E C t hat c o nf or ms 
t o 2 1 C o de of Fe d eral Re g ulati o ns ( C F R) Part 5 6, 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 on.  
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 2 1  C o de of 
Fe deral Re g ulati o ns ( C F R) Part 5 0 , I C H, a n d l ocal re g ul ati o ns, are met. 
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 bj ect/eac h s u bject 
w h o partici pates i n t he tri al, 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/ p e diatric asse nt f or m is t he m ost c urre nt versi 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/ pe diatric asse nt f or m s h o ul d c o ntai n a su bject a ut h oriz ati o n 
secti o n t hat descri bes t h e uses a n d discl os ures of a s u bject’s pers o nal i nf or mati o n (i ncl u di n g 
pers o nal he alt 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 m e d 
c o nse nt/ pe diatric asse nt f or m d oes n ot i ncl u d e 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 s u 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 re c 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 ns 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.  
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 2 9  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
1 1.  Mai ntai n c urre nt rec or ds of t he recei pt, a d mi nistra ti 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 C S R . 
F or n o n- c o m m er ci al u s e o nl y

T a ke d a’s Tetr a v ale nt De n g u e V acci ne C a n di d ate  
 
Tri al N o. D E N -3 0 3  
P a ge 1 3 0  of 1 3 0  
Pr ot oc ol Versi o n 5. 0  
2 2  A u g ust  2 0 2 2  
 
C O N FI D E N TI A L  
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 he r 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 nite d States, 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, processe 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 pa rati 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 ot her vacci n es use d i n ot her cli nical st u dies t hat ma y c o ntai 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 detail s 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 tra nsferre 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 ns e nts t o t he use of his or h er pers o nal 
i nf or mati o n b y T a ke da a n d ot her parties f or t he p ur p oses descri be d a b o v e. 
Please n ote t hat t his c o nse nt will n ot c o ver i n vesti gat or p ers o n n el.  
F or n o n- c o m m er ci al u s e o nl y

Si g nat ure Pa ge f or D E N- 3 0 3 Pr ot oc ol A me n d me nt 3, Versi o n 5. 0, 2 2 A u g ust 2 0 2 2
Title: 
D oc u me nt N u m ber: T A K- 0 0 3- 0 4 2 1 6 v 5. 0
A p pr o val
Statistics
0 1- Se p- 2 0 2 2 1 6: 0 2: 1 4 G M T + 0 0 0 0
A p pr o val
Cli nical
0 1- Se p- 2 0 2 2 1 9: 0 6: 5 4 G M T + 0 0 0 0
A p pr o val
P har mac o vi gila nce
0 2- Se p- 2 0 2 2 0 9: 2 0: 5 1 G M T + 0 0 0 0
A p pr o val
Cli nical
0 5- Se p- 2 0 2 2 0 0: 1 5: 0 8 G M T + 0 0 0 0
F or n o n- c o m m er ci al u s e o nl y