A Phase 4 Study to Assess the Safety and Immunogenicity of VAXCHORA (Cholera Vaccine, Live, Oral) in Children 2 to <18 Years of Age
Phase: PHASE4
Conditions: Cholera (Disorder)
Sponsor: Bavarian Nordic



V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 2  of 6 1  
 
 
P R O T O C O L SI G N A T U R E S H E E T  
A P h ase 4 St u d y t o Assess t he S afet y a n d I m m u n o ge n icit y of V A X C H O R A  (C h oler a V acci ne, 
Li ve, Or al)  i n C hil dre n 2 t o < 1 8 Ye ars of A ge 
 
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt a n d all i nf or mati o n pr o vi de d t o y o u relate d t o 
V A X C H O R A ™ (C h olera Vacci ne, Li ve, Oral ) are t he c o nfi d e ntial a n d pr o prietar y i nf or m ati o n of 
Pa x Va x, I n c. ( S p o ns or) a n d e xce pt as ma y b e re q uire d b y fe deral, state or l ocal la ws or re g ulati o ns, 
ma y n ot be discl ose d t o ot hers wit h o ut pri or writte n per missi o n of S p o ns or. T he Pri nci pal 
I n v esti gat or ma y, h o we v er, discl ose s uc h i nf or m ati o n t o s u per vise d i n di vi d uals w or ki n g o n t he 
St u d y, i ncl u di n g i n di vi d uals wit h a n y I nstit uti o nal Re vie w B oar ds (I R Bs) or I nstit uti o nal 
Bi osafet y C o m mittees (I B Cs), pr o vi de d s uc h i n di vi d uals a gree t o be b o u n d t o mai ntai n t he 
c o nfi de ntialit y of s uc h St u d y Vacci n e i nf or mati o n.  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
I a gree t o a bi de b y t he st ate me nt of c o nfi de ntialit y. 
I a gree t o c o n d uct t he st u d y acc or di n g t o t his pr ot oc ol. A n y c ha n ges i n pr oce d ure will o nl y be 
ma de if necessar y t o pr ot ect t he safet y, ri g hts, or welfare of s u bjects.  
I a gree t o c o m pl y wit h t h e c urre nt I nter n ati o nal C o nfere n ce o n Har m o nizati o n Tri partite G ui deli ne 
o n G o o d Cli nical Practice i n a d diti o n t o t he a p pr o priate F D A C o de of Fe d eral Re g ulati o ns ( C F Rs) 
a n d state a n d l oc al re g ulati o ns.  
I a gree t o c o n d uct t he st u d y i n pers o n or t o s u per vise t he st u d y. 
I a gree t o e ns ur e t hat all t hat assist me i n t he c o n d uct of t he st u d y ha ve access t o t he st u d y pr ot oc ol 
a n d a n y a me n d m e nts a n d are a ware of t heir res p o nsi bil ities i n meeti n g t hese o bli gati o ns. 
 
 
 
Pri nci p al  I n vesti g at or 
( Pri nt N a me) 
 
 
 
 
 
Title  
 
 
 
 
 
Si g n at ure  
 
D ate  

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 3  of 6 1  
P R O T O C O L S Y N O P SI S  
P R O T O C O L TI T L E  
A P hase 4  St u d y t o Assess t he Safet y a n d I m m u n o ge nicit y of 
V A X C H O R A ™ (C h olera Vacci n e, Li ve, Oral ) i n C hil dre n 2 t o < 1 8 
Years of A ge  
SI T E S  
U p t o 3 0 sites i n t he U S  
I N T R O D U C TI O N 
V A X C H O R A (C h olera Vacci n e, Li ve, Oral ) is a vacci ne i n dicate d 
f or acti ve i m m u nizati o n a gai nst disease ca us e d b y Vi bri o c h oler ae  
ser o gr o u p O 1. V A X C H O R A is a p pr o ve d f or use i n a d ults 1 8 
t hr o u g h 6 4 years of a ge tra velli n g t o c h olera-affecte d areas.  
T he pri mar y g oals of t his P hase 4  st u d y are t o e v al uate t he safet y 
a n d i m m u n o ge nicit y of V A X C H O R A i n c hil dre n a ges 2  years t o 
< 1 8 years of a g e  i n de vel o pe d c o u ntries. 
B A C K G R O U N D A N D 
R A TI O N A L E  
C h olera is a n ac ute e nt eric i nf ecti o n ca use d b y t he bacteri u m 
V.  c h oler ae a n d tra ns mitte d b y t he i n gesti o n of water or f o o d 
c o ntai ni n g t he or ga nis m. C h olera is c haracterize d i n its m ost se vere 
f or m (c h olera gra vis) b y a s u d de n o nset of ac ute water y diarr h ea 
t hat ca n lea d t o se v ere de h y drati o n a n d deat h.  
T he  V. c h oler ae, strai n C V D 1 0 3-H g R was d e vel o pe d as a li ve, oral 
vacci ne  f or t he pre v e nti o n of c h olera i n a d ults, a n d lice nse d i n 
se veral c o u ntries e x-U S u n der t he tra d e n a mes Or oc h ol a n d 
M utac h ol . Cli nica l trial e x perie n ce wit h  C V D 1 0 3 -H g R i ncl u des 
a d mi nistrati o n  t o m ore t ha n 2 7, 0 0 0 a d ults a n d c hil dre n as y o u n g as 
3 m o nt hs ol d,  a n d o ver 5 0 0, 0 0 0 c o m mercial d oses of C V D 1 0 3 -
H g R vacci n e  were  s ol d wit h a n i n dicati o n i n tra v elers t w o y ears or 
ol der .  
C V D 1 0 3 -H g R was re de vel o pe d b y Pa x Va x a n d is n o w lice nse d 
u n der t he tra d e na me Va xc h ora ® ( B L A S T N 1 2 5 5 9 7/ 0) f or use i n 
a d ults 1 8 t hr o u g h 6 4 years of a ge w h o are tr a velli n g t o c h olera-
affecte d areas . S afet y dat a fr o m a p pr o xi matel y 3, 0 0 0 a d ult s u bjects 
i n t he V A X C H O R A cli nical de vel o p me nt pr o gra m  s h o w t hat t here 
is ver y little differe nce i n t he fre q ue nc y of react o ge nicit y a n d 
a d verse e ve nts  f or reci pie nts of t he li ve-atte n uate d vacci ne a n d 
reci pie nts of place b o. 
St u die s i n c hil dre n i n b ot h de vel o pe d a n d d e vel o pi n g c o u ntries 
usi n g  a si n gle d ose of  t he C V D 1 0 3-H g R vacci ne strai n s h o we d t hat 
t he vacci ne was well t olerate d. H o we ver,  t here are n o p u blis he d 
st u dies of ser ol o gical res p o nse rates i n c hil dre n i n de vel o p e d 
c o u ntries.  
A C TI V E V A C CI N E   
V A X C H O R A  ( C h olera Vacci n e, Li ve, Oral) is a li ve, atte n uate d 
bacterial vacci ne s us pe nsi o n f or oral a d mi nistrati o n c o ntai ni n g t he 
V. c h oler ae  strai n C V D 1 0 3-H g R. C V D 1 0 3 -H g R was c o nstr ucte d 

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 4  of 6 1  
fr o m t he ser o gr o u p O 1 classical I na ba str ai n 5 6 9 B b y deleti n g t he 
catal ytic d o mai n se q ue n ce of b ot h c o pies of t he ctx A ge ne, w hic h 
pre ve nts t he s y nt hesis of acti ve c h olera t o xi n ( C T). T his atte n uate d 
strai n re mai ns a ble t o s y nt hesize t he i m m u n o ge nic n o n-t oxic B 
s u b u nit of C T (e n c o de d b y t he ctx B ge n e). I n a d diti o n, a mar ker was 
i nserte d i nt o t he h e m ol ysi n ge ne l oc us (hl y A ) t o e na ble 
differe ntiati o n of t he vacci ne strai n fr o m wil d t y p e V. c h oler ae  O 1.  
T his  n o nt o xic B s u b u nit is i m m u n o ge nic a n d ca pa ble of ge n erati n g 
ne utralizi n g a nti b o dies a gai nst t he t o xic acti vit y of t he oli g o meric 
c h olera e nter ot o xi n. A nti bacterial ser u m vi bri oci dal a nti b o dies (a 
s urr o gate of pr ot ecti o n) t hat are direct e d 
mai nl y a gai nst t he 
li p o p ol ysacc hari de O a nti ge n ( b ut als o a gai nst s urface pr ot ei n 
a nti ge ns) are als o i n d u ce d  b y t he li ve v acci ne . V A X C H O R A  is 
pr o vi de d as t w o si n gle-use pac kets, o n e c o ntai ni n g vacci ne as 
l y o p hilize d p o w der a n d o ne c o ntai ni n g bicar b o nate b uffer. T h e 
c o nte nts of b ot h p ac k ets are rec o nstit ute d i n p urifie d b ott le d water 
(Secti o n  4. 1 ). T he res ulta nt s us pe nsi o n is a d mi nistere d orall y at a 
d ose of a p pr o x. 1 x 1 0 9 c ol o n y f or mi n g u nits ( C F U).  
C O N T R O L V A C CI N E  
T he place b o c o ntr ol f or t his st u d y is n or mal ( 0. 9 %) sali ne  
(Secti o n  4. 2 ). 
M O D E O F 
A D MI NI S T R A TI O N  
S u bjects will ta ke n o f o o d or water f or 6 0  mi n utes bef ore a n d after 
vacci nati o n. V A X C H O R A  will be rec o nstit ute d i n p urifie d b ottle d 
water  wit h b uffer  (Secti o n 4. 1 ). V A X C H O R A  a n d place b o will be 
a d mi nistere d orall y.  
O B J E C TI V E S  
1)  De m o nstrate t hat t he ser oc o n versi o n rate  at Da y 1 1 i n  pe diatric 
s u bjects is n o n-i nferi or t o t he ser oc o n versi o n rate at Da y 1 1 i n 
a d ults bet wee n t he a ges of 1 8 a n d  4 5 years.  
2)  De m o nstrate t hat t he ser oc o n versi o n rate i n pe diatric s u bjects is 
greater t ha n or e q u al t o 7 0 % wit h 9 8. 3 % c o nfi de n ce.  
 
T he t w o pri mar y o bjecti v es will be e v al uate d i n d e pe n de ntl y of o n e 
a n ot her i n eac h of t he 3 a ge gr o u ps of c hil dre n acc or di n g t o a 
parallel se q ue ntial d esi g n wit h u nifie d c o ntr ol of t he t otal T y pe I 
err or acr oss all 6 tes ts.  See t he Al p ha-S pe n di n g Str ate g y secti o n f or 
a descri pti o n of t he testi n g de pe n d e ncies a n d t he p artiti o ni n g of t he 
st u d y wise T y pe I err or.  
S T U D Y P O P U L A TI O N  U p t o 5 9 5  healt h y c hil dre n a ges 2  y ears t o < 1 8 years of a ge will be 
e nr olle d i nt o t hree a ge C o h ort s as f oll o ws:  
•  C o h ort 1:  1 2 t o < 1 8  years ( n = 1 5 0 :acti ve treat me nt gr o u p, 
n = 2 5: place b o cr oss o ver  gr o u p  f or 1 7 5 t otal s u bjects) 
•  C o h ort 2:  6 t o < 1 2  years ( n = 1 5 0 :acti ve treat me nt gr o u p, 
n = 2 5: place b o cr oss o ver gr o u p  f or 1 7 5 t otal s u bjects) 
•  C o h ort 3:  2 t o < 6  years ( n = 2 1 0 :acti ve tr eat me nt gr o u p, 
n = 3 5 : place b o cr oss o ver gr o u p f or 2 4 5 t otal s u bjects) 

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 5  of 6 1  
C o h orts ma y be e nr olle d c o nc urre ntl y.  
I ncl usi o n Criteri a: 
1.  Male or fe m ale  
2.  Bet wee n 2 a n d < 1 8 years of a ge o n Da y 1.  
3.  I n g e neral g o o d healt h. 
4.  A ble a n d willi n g t o pr o vi de i nf or me d ass e nt f or st u d y 
partici pati o n.  
5.  Pri mar y care gi ver is a ble a n d willi n g t o pr o vi de i nf or me d 
c o nse nt f or st u d y partici pati o n.  
6.  (f or fe males of c hil d beari n g p ote ntial) Usi n g a n acce pta bl e 
met h o d of c o ntrace pti o n t hr o u g h Da y 2 9 . 
E xcl usi o n Criteri a:   
1.  C urre nt ac ute gastr oi ntesti nal ill ness  or l o ose st o ols wit hi n 
3 da ys of Da y 1 visit . 
2.  C urre nt ac ute fe brile ill n ess.  
3.  Hist or y of c h olera i nfecti o n.  
4.  Hist or y of c h olera vacci n ati o n.  
5.  Hist or y of se v ere aller gi c reacti o n (e. g. a n a p h yla xis) t o a n y 
i n gre die nt of V A X C H O R A.  
6.  C o n ge nital or ac q uire d i m m u n o deficie nc y.  
7.  Pre g na nc y (f or fe males of c hil d beari n g p ote ntial)  
8.  A n y ot her c o n diti o n t hat, i n t he o pi ni o n of t he I n v esti gat or, 
creat es a n u nacce pta ble ris k t o t he s u bject.  
9.  A n y ot her c o n diti o n t hat, i n t he o pi ni o n of  t he I n v esti gat or, 
will i nterfere  wi t h t he c o n d uct of t he st u d y or t he vali dit y of 
t he data. 
1 0.  D urati o n of > 2 wee ks of a b n or mal st o ol patter n, d efi ne d as 
< 3 st o ols per wee k or > 2 st o ols per da y i n t he p ast 6 m o nt hs . 
1 1.  Re g ular use of la x ati ves i n t he past 6 m o nt hs.  
1 2.  Hist or y of e nter ot o xi ge ni c E. c oli  i nfecti o n. 
1 3.  Tra vel t o c h olera -e n de mi c area i n t he pre vi o us 5 years.  
1 4.  N ursi n g/ breastf ee di n g.  
1 5.  Recei ve d or pl a ns t o recei ve t he f oll o wi n g fr o m 1 4 da ys 
pri or t o t he st u d y vacci nati o n t hr o u g h 1 1 da ys after 
vacci nati o n : 
A n y ot her lice nse d v acci nes  
A nti bi otics or c hl or o q ui ne  
1 6.   Recei ve d or pla ns t o recei ve a n y ot her i n v esti gati o nal a ge nt  
t hr o u g h o ut t he mai n st u d y (Da y 1 8 1 ). 
S T U D Y D E SI G N  
T his is a ra n d o mize d, place b o -c o ntr olle d, d o u ble -bli n d, si n gle -
cr oss o ver st u d y wit h t hr ee a ge c o h orts a n d t w o treat me nt gr o u ps 
wit hi n eac h c o h ort .  
C o h orts will be e nr olle d c o nc urre ntl y. T he Safet y 
M o nit ori n g 
C o m mittee ( S M C ) will c o n d uct re g ular peri o dic re vie w s of  all 

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 6  of 6 1  
a vaila ble i nteri m, bli n de d safet y data fr o m si m ulta ne o us e nr oll me nt 
of all a ge c o h orts.   
T he mai n st u d y c o nsists of a scree ni n g peri o d of 3 0 da ys, Da y 1 
vacci nati o n, an o bser vati o n  peri o d fr o m Da y 1 t o Da y 2 9, a n d a 
f oll o w-u p peri o d t hr o u g h Da y 1 8 1. Place b o cr oss o ver has a n 
o pti o nal acti ve vacci nati o n at Da y 1 8 1 aft er u n bli n di n g, wit h a 6 
m o nt h  p ost vacci nati o n f oll o w -u p peri o d  (t o Da y 3 6 5). C o h ort  1 has 
a n o pti o nal s u b -st u d y c o nsisti n g of a l o n g-ter m f oll o w-u p peri o d 
t hr o u g h Da y 7 3 0.   
I n eac h c o h ort, s u bj ects will be ra n d o mize d i n a 6 : 1 rati o t o t he 
Acti ve treat me nt gr o u p or t he Place b o cr oss o v er gr o u p.  T he Acti ve 
treat me nt gr o u p will recei ve V A X C H O R A o n Da y 1 a n d t he 
Place b o cr oss o v er gr o u p will recei ve place b o o n Da y 1.  
All s u bjects will ha ve st u d y  vis its at Da ys 1, 1 1, 2 9 a n d 1 8 1. 
Ra n d o mize d treat me nt assi g n me nts will be u n bli n de d at Da y  1 8 1 . 
S u bjects i n C o h ort 1 will ha ve i n-cli nic visits o n Da y 9 1. S u bjects 
i n C o h orts 2 a n d 3 will ha ve f oll o w -u p calls o n Da y 9 1.  S u bjects 
i n t he Place b o cr oss o v er gr o u p will recei ve V A X C H O R A after 
u n bli n di n g at Da y 1 8 1  if t he y s o c h o ose a n d will t he n ha ve st u d y 
visits o n Da ys  1 9 1  a n d 2 0 9  a n d p h o ne calls at Da ys 2 7 1 a n d 3 6 5 .  
After c o m pleti o n  of t he mai n st u d y o n Da y 1 8 1, s u bjects  i n t he 
acti ve treat me nt gr o u p of  C o h ort 1 ma y partici pate ( b y se parate 
i nf or me d asse nt a n d c o nse nt) i n a l o n g-ter m f oll o w-u p s u b -st u d y 
wit h st u d y visits at Da ys 3 6 5, 5 4 7 , a n d 7 3 0. T he t otal d urati o n of 
st u d y partici pati o n is t heref ore u p t o 3 6 5 da ys ( 5 2 wee ks)  f or t he 
mai n st u d y a n d u p t o 7 6 0 da ys ( 1 0 9 wee ks) f or C o h ort 1 s u bjects 
w h o partici pate i n b ot h t he mai n st u d y a n d t he s u b -st u d y.  
St u d y treat me nts are s h o w n i n  Ta ble 3 .  T he St u d y Desi g n is s h o w n 
i n Fi g ure 1 . 
Pri mar y C o m parat or Gr o u p f or All A ge C o h orts: H ealt h y a d ult  
s u bjects, a ge 1 8-4 5 y ears  w h o recei ve d 
a si n gle d ose of  
V A X C H O R A  w hile p artici pati n g i n t he P X V X -V C -2 0 0 -0 0 4 l ot 
c o nsiste nc y trial.   
S T U D Y 
P R O C E D U R E S  
S afet y :  
S u bjects will be m o nit ore d f or ac ute reacti o ns f or 3 0 mi n utes after 
vacci nati o n. A d verse e ve nts  of a b d o mi nal pai n,  h ea dac he, lac k of 
a p petite, tire d ness, diarr hea, na usea, v o miti n g a n d fe ver will be 
s olicite d dail y t hr o u g h Da y  8 (a n d fr o m Da y 1 8 1 t hr o u g h Da y 1 8 8 
f or Place b o cr oss o ver s u bjects) usi n g a me m or y ai d  ( diar y car d). 
U ns olicite d A d verse E v e nts ( A Es) will be c ollect e d t hr o u g h Da y 
2 9 , a n d Da y 1 8 1 t hr o u g h Da y 2 0 9 (f or Place b o cr oss o ver s u bjects). 
Seri o us A d verse E ve nts ( S A Es) will be c ollecte d f or t he d urati o n of 

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 7  of 6 1  
st u d y partici pati o n. I n C o h orts 2 a n d 3, e ve nts occ urri n g after Da y 
2 9 will be assesse d i nit iall y b y tele p h o ne c o ntact.                                                        
I m m u n o ge nicit y: 
I m m u n o ge nicit y 
will b e assesse d b y 
meas ure me nt of S er u m 
V i bri oci dal A nti b o dies ( S V A) i n all s u bjects at Da y s 1, 1 1, a n d 2 9.  
S u bjects i n C o h ort 1 will ha ve f urt her meas ure me nts of S V A at 
Da ys 9 1 a n d 1 8 1 . I n t he s u b-st u d y, s u bjects will ha ve S V A 
meas ure me nts at D a ys 3 6 5, 5 4 7 , a n d 7 3 0.  
St u d y 
pr oce d ures are s h o w n i n t he 
Sc he d ule 
of 
E ve nts 
(A p pe n di x  A ) 
E N D P OI N T S  
1)  C o h ort 1: 1 2 t o < 1 8 y e a rs  
Pri m ar y  E n d p oi nt:  
•  T he pr o p orti o n of s u bjects ac hie vi n g ser oc o n v ersi o n of 
S V A a gai nst t he classical I na ba bi ot y pe of V. c h oler ae  at 
Da y 1 1 f oll o wi n g o ne d o se of V A X C H O R A, d efi ne d as a 4 -
f ol d or great er rise o v er baseli ne Da y 1 S V A titer . T his 
pr o p orti o n of s er oc o n v erters is calle d t h e ser oc o n versi o n 
rate.  
 Sec o n d ar y E n d p oi nts:  
•  S er oc o n versi o n  of  S V A  a gai nst t he classical I na b a bi ot y pe 
of  V . ch oler a e at Da ys 2 9 , 9 1 a n d 1 8 1 f or all s u bjects.  
•  S er oc o n versi o n  of  S V A a gai nst t he classical I na b a bi ot y pe 
of V . ch oler a e at Da ys 3 6 5, 5 4 7 a n d 7 3 0 f or vacci nees 
partici pati n g i n t he s u b -st u d y. 
E x pl or at or y E n d p oi nt: Ass oci ate d me m or y B cell e n d p oi nts:  
•  A nti – O 1 li p o p ol ysacc hari de ( L P S) 
me m or y 
B 
cell 
c o nce ntr ati o n at Da ys 1, 9 1, 1 8 1  f or t he s u bjects i n t he acti ve 
treat me nt gr o u p a n d t he place b o cr oss o ver gr o u p, a n d Da ys  
3 6 5, 5 4 7, 7 3 0  f or t he s u bjects i n t he acti ve treat m e nt gr o u p 
w h o partici pate i n t he s u b -st u d y. 
 
2) C o h ort 2: 6 t o < 1 2 ye ars  
Pri m ar y  E n d p oi nt:  
•  T he pr o p orti o n of s u bjects ac hie vi n g ser oc o n v ersi o n of 
S V A a gai nst t he classical I na ba bi ot y pe of V. c h oler ae  at 
Da y 1 1 f oll o wi n g o ne d ose of V A X C H O R A, d efi ne d as a 4 -
f ol d or great er rise o v er baseli ne Da y 1 S V A titer.  
Sec o n d ar y E n d p oi nt:   
•  S er oc o n versi o n  of S V A a gai nst t he classical I na b a  bi ot y pe 
of  V. 
c h oler ae  at 
Da y 2 9 f oll o wi n g o ne d ose of 
V A X C H O R A . 
 
 
3) C o h ort 3:  2  t o <6  y e ars  

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 8  of 6 1  
Pri m ar y  E n d p oi nt:  
•  T he pr o p orti o n of s u bjects ac hie vi n g ser oc o n v ersi o n of 
S V A a gai nst t he classical I na ba bi ot y pe of V. c h oler ae  at 
Da y 1 1 f oll o wi n g o ne d ose of V A X C H O R A, d efi ne d as a 4 -
f ol d or great er rise o v er baseli ne Da y 1 S V A titer.  
Sec o n d ar y E n d p oi nt:  
•  S er oc o n versi o n  of  S V A a gai nst t he classical I na b a  bi ot y pe 
of  V. 
c h oler ae  at 
Da y 2 9 f oll o wi n g o ne d o se of 
V A X C H O R A . 
 
S afet y : E val uate t he safet y a n d t olera bilit y of V A X C H O R A usi n g 
t he f oll o wi n g e n d p oi nts: 
•  S olicite d ad verse eve nts t hr o u g h Da y 8 : a b d o mi nal pai n, 
hea dac he, lac k of a p petite, tire d ness, diarr hea, na usea, 
v o miti n g a n d fe ver, b y a ge c o h ort a n d o v erall  
•  U ns olicite d ad verse eve nts t hr o u g h Da y 2 9 , b y a ge c o h ort 
a n d o verall  
•  Seri o us ad verse eve nts t hr o u g h Da y 1 8 1, b y a ge c o h ort a n d 
o verall  
Acce pt a bilit y:  E va l uat e t he acce pta bilit y of V A X C H O R A  usi n g 
t he f oll o wi n g e n d p oi nt. 
•  T he perce nt of s u bjects i n eac h a ge c o h ort a ble t o c o m ple te 
t he d osi n g acc or di n g t o pr ot oc ol  
P al at a bilit y:  E val uate t he palata bilit y of V A X C H O R A  usi n g t he 
f oll o wi n g e n d p oi nts: 
•  Palata bilit y of vacci ne assesse d b y t he s u bject usi n g a 5 -p oi nt 
H e d o nic scal e i n C o h orts 1 a n d 2 . 
•  Palata bilit y of vacci ne assesse d b y t he care gi v er usi n g a 
5 -p oi nt He d o nic scal e i n C o h ort 3 . 
S T A TI S TI C A L 
M E T H O D S  
S olicite d A E s will be s u m marize d b y t he p erce nt of s u bjects b y 
treat me nt gr o u p w h o e x perie nce eac h s olicite d a d verse e ve nt at 
least o nce. 
A sec o n d ta ble 
will prese nt a si milar s u m mar y 
c o nstrai ne d t o s olicite d A Es of m o derate se verit y or hi g her. A n 
a d diti o nal a nal ysis will s u m marize t he n u m b er of da ys t hat s u bjects 
e x perie n ce s olicite d A Es.  
U ns olicite d A Es  rec or de d t hr o u g h Da y 2 9 will be s u m marize d b y 
treat me nt gr o u p, s yste m or ga n class, preferre d t er m a n d se verit y.  
A list of a n y S A Es rec or de d t hr o u g h Da y 1 8 1 or later will be 
prese nte d se p aratel y.  
Ser oc o n versi o n will be d efi ne d as a 4 -f ol d or greater ris e i n S V A 
o ver Da y 1 ( baseli ne). Eac h rate will be acc o m pa nie d b y a 9 5 % 
c o nfi de nce i nter val ( CI) calc ulate d usi n g t he 
Wils o n 
met h o d 
(A gresti 1 9 9 8 ). C u m ulati ve ser oc o n versi o n t hr o u g h a partic ular 

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 9  of 6 1  
visit is defi ne d as t he occ urre n ce of ser oc o n v ersi o n at or pri or t o 
t hat visit. 
S V A le vels will be s u m m arize d b y t he ge o m etric mea n titer ( G M T) 
of a nti b o dies a gai nst t he classical I na b a bi ot y pe of V. ch oler ae  at 
all ti me p oi nts f or w hic h a nti b o d y assess me nts are a vaila ble. Eac h 
G M T will be acc o m pa nie d b y a 9 5 % c o nfi de nce i nter val calc ul ate d 
b y first c o nstr ucti n g a c o nfi de nce i nter val o n l o g -tra nsf or me d data 
a n d t he n bac k -tr a nsf or mi n g t he e nd p oi nts of t he c o nfi de nce i nter val 
t o t he ori gi nal data s pace.  
T he relati ve i ncrease i n S V A at a gi ve n p ost -baseli ne ti me p oi nt will 
be s u m marize d usi n g t he ge o metric mea n of t he f ol d -i ncreas e i n 
titer ( G M FI) bet wee n b aseli ne a n d t he ti me p oi nt. A 9 5 % c o nfide nce 
i nter val f or eac h G M FI will be c o nstr ucte d usi n g t he sa me l o g-
tra nsf or mati o n met h o d as t hat use d t o b uil d c o nfi de nce i nter vals f or 
G M Ts.  
Pri m ar y A n al ys es 
1)  T he ser oc o n v ersi o n rate bet wee n Da y 1 a n d Da y 1 1 f or 
vacci nes i n eac h of t he 3 a ge c o h orts will be c o m pare d t o 
t he ser oc o n v ersi o n rate f or vacci nes b et wee n t he a ges of 1 8 
a n d 4 5 
w h o parti cipat e d i n t he l ot c o nsiste nc y st u d y 
P X V X -V C -2 0 0 -0 0 4 b y calc ulati n g t he differe nce bet w ee n 
t he t w o rates a n d c o m p uti n g a 9 6. 7 % c o nfi de nce i nter val f or 
t his differe nce.  
2)  F or eac h o f t he 3 a ge c o h orts, t he pr o p orti o n of v acci nat e d 
s u bjects w h o e x peri e nce a 4-f ol d or great er i n creas e i n 
ser u m vi brioci dal titer b et wee n Da y 1 a n d Da y 1 1 will be  
calc ulate d, a n d a 9 8. 3 % c o nfi de nce i nter val o n t his 
pr o p orti o n of ser oc o n vert ers will be c o m p ute d.  
Acce pt a nce Crit eri a  f or Pri m ar y A n al yses 
1)  T he  l o wer b o u n d  of  t he t w o-si de d 9 6. 7 %  c o nfi de n ce  i nter val 
o n  t he differe nce  i n ser oc o n versi o n rates bet wee n c hil dre n  
a n d a d ults  m ust  be  greater  t ha n -1 0  perce nta ge  p oi nts.  
2)  T he  l o wer b o u n d  of  t he t w o-si de d 9 8. 3 %  c o nfi de n ce  i nter val 
o n  t he pr o p orti o n  of  vacci nees  w h o  ser oc o n vert bet wee n  
Da y  1  a n d Da y  1 1  m ust  e q ual or  e xcee d 7 0 %.  
Al p h a -S pe n di n g Str ate g y  
I n or der  t o e ns ure t hat t he t otal T y pe I err or f or t he st u d y is ca p pe d 
at al p ha =  0. 0 5,  2/ 3  of  t he al p ha will  be  all otte d t o t he pri mar y  
o bjecti ve  of  esta blis hi n g  n o n -i nferi orit y relati ve t o a d ults, a n d 
1/ 3  of  t he al p ha will be  all otte d t o t he pri mar y  o bjecti ve  of  
de m o nstrati n g  t hat t he ser oc o n versi o n rate e q uals  or  e xcee ds  
7 0 %.  
T he  t w o pri mar y  o bjecti ves  will  be  e val uate d  
i n de pe n de ntl y, a n d wit hi n  eac h pri mar y  o bjecti ve,  testi n g i n t he 
differe nt  a ge c o h orts will  pr ocee d  se q ue ntiall y be gi n ni n g  wit h  

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 1 0  of 6 1  
t he data  f or t he 1 2  t o < 1 8  a ge c o h ort, as f oll o ws: 
1)  
N o n -i nferi orit y: t he a nal ysis  of  n o n -i nferi orit y bet wee n  
vacci nees  i n t he 1 2 -1 8  a ge c o h ort a n d a d ults bet wee n  t he 
a ges of  1 8  a n d 4 5  will  be  c o n d ucte d  first. F or mal  a nal ysis 
of  n o n -i nf eri orit y i n t h e 6  t o < 1 2  a ge c o h ort will  be  
perf or me d  o nl y  if t he l o wer b o u n d  of  t he t w o-si de d 9 6. 7 %  
c o nfi de nce i nter val o n  t he differe nce  bet wee n  
t he 
ser oc o n versi o n rates f or c hil dre n i n t he 1 2  t o < 1 8  a ge c o h ort 
a n d a d ults e q uals  or  e xcee ds  t he pre -s pecifie d acce pta nce 
criteri o n. F or mal  e val uati o n  of  n o n -i nferi orit y i n t he 2  t o 
< 6  a ge c o h ort will  occ ur  o nl y  if t he acce pta nce criteri o n  is 
met  f or b ot h  t he 1 2  t o < 1 8  a n d 6  t o < 1 2  a ge c o h orts.  T his  
strate g y mai ntai ns  t he o verall  T y pe  I err or f or t he pri mar y  
o bjecti ve  of  n o n -i nferi orit y at al p ha =  0. 0 3 3.  
2)  
Ser oc o n versi o n  Rate:  t he a nal ysis of  t he ser oc o n versi o n 
rate a m o n g vacci nees  i n t he 1 2  t o < 1 8  a ge c o h ort  will  be  
c o n d ucte d  first. F or mal  a nal ysis  of  t he acce pta bilit y of  t he 
ser oc o n versi o n rate i n t he 6  t o < 1 2  a ge c o h ort will  be  
perf or me d  o nl y  if t he l o wer b o u n d  of  t h e t w o-si de d 9 8. 3 %  
c o nfi de nce i nter val o n  t he ser oc o n versi o n rate i n t he 1 2  t o 
< 1 8  a ge c o h ort meets  t he pre -s pecifie d acce pta nce 
criteri o n. F or mal e val uati o n of t he acce pta bilit y of t he 
ser oc o n versi o n rate i n t he 2 t o < 6 a ge c o h ort will occ ur o nl y 
if t he acce pta nce criteri o n is met f or b ot h t he 1 2 t o < 1 8 a n d 
6 t o < 1 2 a ge c o h orts. T his strate g y mai ntai ns t he o verall 
T y pe I err or f or t he pri mar y o bjecti ve  c o ncer ni n g t he 
ma g nit u de of t he ser oc o n versi o n rate at al p ha = 0. 0 1 7.  
Sec o n d ar y A n al yses  
F or vacci nees i n t he a ge co h ort 1 2 t o < 1 8, t he p oi nt esti mate of t he 
ser oc o n versi o n rate f or vacci nees as 
well as t he c u m ulati ve 
ser oc o n versi o n rate will be c o m p ute d  at t he ti me  p oi nts Da y 2 9, 
Da y  9 1 a n d Da y 1 8 1, a n d a 9 5 % c o nfi d e nce i nter val will be 
c o nstr ucte d f or eac h pr o p orti o n.  P oi nt wise ser oc o n versi o n rates, 
c u m ulati ve ser oc o n versi o n rates, a n d c o nfi de n ce i nter vals f or 
place b o reci pie nts i n t h e a ge c o h ort 1 2 t o < 1 8 will be c o m p ute d at 
Da y 1 1, Da y 2 9, Da y 9 1 a n d Da y 1 8 1. F or vacci nees i n t he a ge 
co h orts 2 t o < 6 a n d 6 t o < 1 2, p oi nt wise a n d c u m ulati ve 
ser oc o n versi o n rates a n d c orres p o n di n g c o nfi de nce i nter vals will be 
calc ulate d f or Da y 2 9. P oi nt w ise ser oc o n versi o n rates, c u m ulati ve 
ser oc o n versi o n rates, a n d c o nfi de nce i nter vals f or place b o 
reci pie nts i n t he a ge c o h orts 2 t o < 6 a n d 6 t o < 1 2 will be c o m p ute d 
at Da y 1 1 a n d Da y 2 9.   
F or v acci nees a n d pl ace b o reci pie nts i n t he a ge co h ort 1 2 t o < 1 8, 
t he G M T a n d 9 5 % c o nfi de nce i nter val will be c o m p ute d f or Da y 1, 
Da y 1 1, Da y 2 9, Da y 9 1 a n d Da y 1 8 1, a n d t he G M FI i n eac h 

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 1 1  of 6 1  
treat me nt gr o u p will be calc ulate d f or Da y 1 1, Da y 2 9, Da y 9 1 a n d 
Da y 1 8 1.  F or vacci nees a n d place b o reci pie nts i n t he a ge co h orts  2 
t o < 6 a n d 6 t o < 1 2, G M Ts a n d 9 5 % c o nfi de n ce i nter vals  will be 
calc ulate d f or Da y 1, Da y 1 1 a n d Da y 2 9 , a n d G M FIs a n d 
c orres p o n di n g c o nfi de nce i nter vals will be calc ul ate d f or Da y 1 1 
a n d Da y 2 9 . F or partici pa nts i n t he s u b-st u d y, t h e G MT a n d 9 5 % 
c o nfi de nce i nter val a n d G M FI wit h 9 5 % c o nfi de nce i nter val will be 
calc ulate d f or Da ys 3 6 5, 5 4 7 a n d 7 3 0.  
Me m or y B C ell C o nce ntr ati o n A n al yses  
I n t h e mai n st u d y, anti -O 1 L P S me m or y B cells will be assesse d at 
Da y s 1 , 9 1 a n d 1 8 1 f or a s u bset of s u bjects i n C o h ort 1 a n d at Da ys 
3 6 5, 5 4 7, a n d 7 3 0 f or s u bjects i n t he acti ve treat me nt gr o u p i n 
C o h ort 1  w h o are partici pati n g i n t he s u b -st u d y. P oi nt esti mates of 
me dia n perce nta ge as well as me dia n f ol d rise fr o m Da y 1 t o Da y 
9 1, Da y 1 8 1 , 3 6 5, 5 4 7, 7 3 0 will be prese nte d.  
S a m ple Size R ati o n ale  
Ass u mi n g t hat t he tr ue ser oc o n versi o n rate a m o n g 1 2 t o < 1 8 -year -
ol ds is 9 2. 4 % or hi g her, t he sa m ple size  of 1 4 3 e val ua ble  vacci nees 
f or t hat a g e c o h ort aff or ds 93 . 3 % p o wer t o de m o nstrate t hat t he 
ser oc o n versi o n rat e wit hi n t he gr o u p is n o n-i nferi or t o t he 9 4 % rat e 
o bser ve d i n t he 2 6 8 7 a d ult s u bjects assess e d i n t he Pa x Va x l ot -
c o nsiste nc y trial, P X V X -V C -2 0 0 -0 0 4. T h e sa m ple size t o be 
e nr olle d all o ws f or u p t o 5 % of s u bjects n ot e val ua ble f or t he 
p rimar y i m m u n o ge nicit y a nal yses i n t he t w o ol der c o h orts (a g es 6 
t o < 1 8). Base d o n t he i ne val ua ble rate o bser ve d t o  date , it is 
esti mate d t hat a p pr o xi matel y 3 0 % of s u bjects i n t he y o u n gest 
c o h ort (a g es 2 t o < 6)  will be i ne val ua ble, m ostl y d ue t o lac k of 
c o ns u m pti o n of t he f ull d ose . Ma ki n g si milar ass u m pti o ns a b o ut t he 
tr ue ser oc o n versi o n rates i n t he ot her t w o p e diatric a ge c o h orts, a n d 
ass u mi n g t hat t he rates i n t he  t hree a ge c o h orts are i n de pe n de nt of 
o ne a n ot her, t he o verall p o wer f or d e m o nstrati n g t he n o n -i nf eri orit y 
of all t hree a ge c o h orts is ( 9 3 . 3 %)3 = 8 1 %.  
U n der t he sa me ass u m pti o ns as a b o ve –  i n partic ular, ass u mi n g t he 
tr ue ser oc o n versi o n rate wit hi n a n a ge c o h ort is at least 9 2. 4 % –  1 4 3 
e val ua ble  vacci nees pr o vi de greater t ha n 9 9. 9 % p o wer t o esta blis h 
t hat t he l o wer b o u n d o n t he c o h ort-s pecific rate is at least 7 0 %. 
P o wer is still greater t ha n 9 9. 9 % w he n re q uiri n g t he l o wer b o u n d 
o n all t hree c o h orts t o be 7 0 % or greater.  
T he o verall p o wer of meeti n g b ot h pri mar y o bjecti ves i n all t hree 
a ge c o h orts ca n be a p pr o xi mate d b y m ulti pl yi n g  t he p o wer of 
meeti n g t he n o n -i nferi orit y o bjecti ve b y t he p o wer of m eeti n g t he 
7 0 % l o wer b o u n d o bjecti ve: 8 1 % x 9 9. 9 % ≈ 8 1 %.  
Gi ve n a t otal of 5 1 0 s u bjects recei ve V A X C H O R A , t here is a 9 9 % 
c ha nce t hat a n u nc o m m o n A E - o ne e x pecte d t o occ ur i n o nl y 1 % 
of vacci n ees - will be o bs er ve d at least o nce d uri n g t he trial.  

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 1 2  of 6 1  
 
 
 
I nteri m A n al ysis 
After t he last s u bjects e nr olle d i n C o h orts 1 a n d 2 ha ve c o m plete d 
t heir Da y 1 8 1 visit, a preli mi nar y i m m u n o ge nicit y a n d safet y 
a nal ysis 
ma y be perf or me d a n d re p ort writte n t o facilitate a 
re g ulat or y s u b missi o n.   

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 1 3  of 6 1  
T A B L E O F C O N T E N T S  
P a ge  
P R O T O C O L SI G N A T U R E S H E E T  .....................................................................................2  
P R O T O C O L S Y N O P SI S  ........................................................................................................3  
1  
I N T R O D U C TI O N......................................................................................................1 8  
1. 1  
Bac k gr o u n d  ......................................................................................................1 8  
1. 1. 1  
Na me a n d D escri pti o n of Acti ve Vacci ne  ........................................1 9  
1. 1. 2  
S u m mar y of Fi n di n gs fr o m N o ncli nical St u dies  ..............................2 0  
1. 1. 3  
S u m mar y of Fi n di n gs fr o m Cli nical St u dies  ....................................2 1  
1. 2  
Rati o nale f or t he C urre nt St u d y  .......................................................................2 2  
1. 2. 1  
Rati o nale f or D osa g e a n d R o ute of A d mi nistrati o n  ..........................2 2  
1. 2. 2  
Rati o nale f or Pe diatric St u d y  ............................................................2 3  
2  
O B J E C TI V E S A N D E N D P OI N T S  ..........................................................................2 3  
2. 1  
I m m u n o ge nicit y O bje cti ves a n d E n d p oi nts .....................................................2 3  
2. 2  
Safet y O bjecti ve a n d E n d p oi nts  .......................................................................2 4  
2. 3  
Acce pt a bilit y  ....................................................................................................2 5  
2. 4  
Palata bilit y  .......................................................................................................2 5  
3  
S T U D Y P L A N  ............................................................................................................2 5  
3. 1  
St u d y Desi g n  ....................................................................................................2 5  
3. 2  
N u m ber of St u d y Partici pa nts  ..........................................................................2 7  
3. 3  
Esti mate d St u d y D urati o n  ................................................................................2 7  
3. 4  
St u d y P o p ulati o n  ..............................................................................................2 7  
3. 4. 1  
I ncl usi o n Criteria  ..............................................................................2 7  
3. 4. 2  
E xcl usi o n Criteria  .............................................................................2 7  
4  
S T U D Y V A C CI N E  ....................................................................................................2 8  
4. 1  
V A X C H O R A  ...................................................................................................2 8  
4. 2  
Place b o  .............................................................................................................2 9  
4. 3  
St u d y Vacci ne Acc o u nta bilit y  .........................................................................2 9  
4. 4  
St u d y Vacci ne Dis pe nsi n g  ...............................................................................2 9  
5  
S T U D Y  P R O C E D U R E S  ...........................................................................................3 0  
5. 1  
I nf or me d C o nse nt.............................................................................................3 0  
5. 2  
Scree ni n g Pr oce d ure  ........................................................................................3 0  
5. 3  
Re -Scree ni n g Pr oce d ure ...................................................................................3 0  

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 1 4  of 6 1  
5. 4  
Ra n d o mizati o n Pr oce d ure  ................................................................................3 0  
5. 5  
Bli n di n g Safe g uar ds  .........................................................................................3 1  
5. 6  
Me dical Hist or y  ...............................................................................................3 1  
5. 7  
P h ysical E xa mi nati o n .......................................................................................3 1  
5. 8  
Vital Si g ns  ........................................................................................................3 2  
5. 9  
Pre g na nc y T esti n g a n d C o ntrace pti o n  .............................................................3 2  
5. 1 0  
Vacci n ati o n  ......................................................................................................3 2  
5. 1 1  
Acce pt a bilit y a n d Palata bilit y Assess me nts  .....................................................3 3  
5. 1 2  
I m m u ne Res p o ns e Assess me nts ......................................................................3 3  
5. 1 3  
S olicite d A d verse E ve nts  .................................................................................3 3  
5. 1 4  
A d verse E v e nts  ................................................................................................3 4  
5. 1 5  
Pri or a n d C o nc o mita nt Me dicati o ns  ................................................................3 4  
5. 1 6  
Pr o hi bite d Me dicati o ns  ....................................................................................3 4  
5. 1 7  
E mer ge nc y U n bli n di n g  ....................................................................................3 4  
5. 1 8  
Pr ot oc ol De viati o ns  ..........................................................................................3 4  
5. 1 9  
C o m pleti o n of St u d y Partici pati o n f or I n di vi d ual S u bjects  .............................3 5  
5. 2 0  
Earl y Disc o nti n uati o n  ......................................................................................3 5  
5. 2 1  
S u bject Re place me nt  ........................................................................................3 5  
5. 2 2  
St u d y C o m pleti o n  ............................................................................................3 5  
6  
S T U D Y P R O C E D U R E S B Y VI SI T  .........................................................................3 6  
6. 1  
St u d y Visits  ......................................................................................................3 6  
6. 1. 1  
Scree ni n g Visit ( -3 0 Da ys t o Da y 1)  .................................................3 6  
6. 1. 2  
Da y 1  .................................................................................................3 6  
6. 1. 3  
Da y 1 1  ...............................................................................................3 7  
6. 1. 4  
Da y 2 9 ( ± 2)  .......................................................................................3 7  
6. 1. 5  
Da y 9 1 ( ± 7):  .....................................................................................3 7  
6. 1. 6  
Da y 1 8 1 ( ± 7 da ys): U n bli n de d  .........................................................3 8  
6. 1. 7  
Da y 1 9 1 ( 1 0 da ys after acti ve vacci nati o n): f or Place b o cr oss o ver 
gr o u p o nl y  .........................................................................................3 9  
6. 1. 8  
Da y 2 0 9 ( ± 2) ( 2 8 d a ys after acti ve v acci n ati o n): f or Place b o 
cr oss o ver gr o u p o nl y  .........................................................................3 9  
6. 1. 9  
Da y 2 7 1 ( ± 7) ( 9 0 d a ys after acti ve v acci n ati o n): f or Place b o 
cr oss o ver gr o u p o nl y  .........................................................................3 9  

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 1 5  of 6 1  
6. 1. 1 0  
Da y 3 6 5 ( ± 7) ( 6 m o nt hs after acti ve vacci nati o n): f or Place b o 
cr oss o ver gr o u p o nl y  .........................................................................3 9  
6. 1. 1 1  
Da y 3 6 5 ( ± 1 4 da ys) f or l o n g ter m f oll o w -u p gr o u p (s u b -st u d y f or 
C o h ort 1 o nl y)  ...................................................................................3 9  
6. 1. 1 2  
Da y 5 4 7 ( ± 1 4 da ys) f or l o n g ter m f oll o w -u p gr o u p (s u b -st u d y f or 
C o h ort 1 o nl y)  ...................................................................................3 9  
6. 1. 1 3  
Da y 7 3 0 ( ± 1 4 da ys) f or l o n g ter m f oll o w -u p gr o u p (s u b -st u d y f or 
C o h ort 1 o nl y)  ...................................................................................4 0  
6. 2  
Earl y Disc o nti n uati o n Visit  ..............................................................................4 0  
6. 3  
U nsc he d ule d Visits  ..........................................................................................4 0  
7  
S A F E T Y  ......................................................................................................................4 1  
7. 1  
Defi niti o ns ........................................................................................................4 1  
7. 1. 1  
A d verse E v e nt  ...................................................................................4 1  
7. 1. 2  
S olicite d A d verse E ve nt  ....................................................................4 1  
7. 1. 3  
U ns olicite d A d verse E v e nt  ...............................................................4 2  
7. 1. 4  
Seri o us A d verse E v e nt  ......................................................................4 2  
7. 2  
Se verit y Gra di n g  ..............................................................................................4 2  
7. 3  
Ca usalit y Assess me nt .......................................................................................4 3  
7. 4  
F oll o w -u p of A d v erse E v e nts  ..........................................................................4 3  
7. 5  
Re p orti n g of A d vers e E v e nts  ...........................................................................4 3  
7. 5. 1  
Re p orti n g Peri o ds ..............................................................................4 3  
7. 5. 2  
D oc u me ntati o n  ..................................................................................4 4  
7. 6  
S A E Re p orti n g  .................................................................................................4 4  
7. 7  
Ot her E ve nts Re q uiri n g I m me diate Re p orti n g  ................................................4 5  
7. 7. 1  
Pre g na nc y  ..........................................................................................4 5  
7. 7. 2  
D osi n g Err ors  ....................................................................................4 5  
7. 7. 3  
Earl y Disc o nti n uati o n f or Safet y Reas o ns  ........................................4 5  
7. 7. 4  
E mer ge nc y U n bli n di n g f or Safet y Reas o ns  ......................................4 5  
7. 8  
Me dical M o nit or  ..............................................................................................4 5  
7. 9  
Safe t y M o nit ori n g C o m mittee ( S M C) .............................................................4 6  
7. 1 0  
St u d y St o p pi n g R ules  .......................................................................................4 6  
8  
D A T A H A N D LI N G  ...................................................................................................4 7  
8. 1  
S o urce D oc u m e ntati o n  .....................................................................................4 7  
8. 2  
Case Re p ort F or ms  ...........................................................................................4 7  

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 1 6  of 6 1  
8. 3  
Rete nti o n of St u d y D oc u me ntati o n  ..................................................................4 7  
8. 4  
Data M o nit ori n g  ...............................................................................................4 7  
8. 5  
La b orat or y Data  ...............................................................................................4 7  
8. 6  
A u dit C o m plia nce  ............................................................................................4 8  
9  
S T A TI S TI C A L A N A L Y SI S  .....................................................................................4 9  
9. 1  
Sa m ple Size Calc ulati o n  ..................................................................................4 9  
9. 2  
Treat me nt Peri o d  ..............................................................................................4 9  
9. 3  
Treat me nt Gr o u ps  ............................................................................................4 9  
9. 4  
Safe t y A nal ysis ................................................................................................5 0  
9. 4. 1  
S olicite d A Es  ....................................................................................5 0  
9. 4. 2  
U ns olicite d A Es  ................................................................................5 0  
9. 5  
I m m u n o ge nicit y A n al ysis ................................................................................5 0  
9. 5. 1  
Pri mar y I m m u n o ge ni cit y A nal yses ...................................................5 0  
9. 5. 2  
Sec o n dar y A n al yses  ..........................................................................5 1  
9. 5. 3  
Me m or y B Cell C o nce ntrati o n A nal yses  ..........................................5 2  
9. 6  
I nteri m A nal ysis ...............................................................................................5 2  
1 0  
A D DI TI O N A L I N F O R M A TI O N  .............................................................................5 3  
1 0. 1  
Et hical C o n d uct of t he St u d y  ...........................................................................5 3  
1 0. 2  
I R B O versi g ht ..................................................................................................5 3  
1 0. 3  
I nf or me d C o nse nt a n d Asse nt ..........................................................................5 3  
1 0. 4  
S u bject C o nfi de ntialit y  ....................................................................................5 3  
1 0. 5  
C o m pe nsati o n f or I nj ur y  ..................................................................................5 4  
1 0. 6  
Cli nicaltrials. g o v  ..............................................................................................5 4  
1 0. 7  
P u bli c Discl os ure a n d P u blicati o n P olic y  ........................................................5 4  
1 0. 8  
A me n d me nts  ....................................................................................................5 4  
1 0. 9  
A n n ual Pr o gress Re p ort  ...................................................................................5 4  
1 0. 1 0  E n d of St u d y Re p ort .........................................................................................5 4  
A P P E N DI X A: S C H E D U L E O F E V E N T S  .........................................................................5 5  
A P P E N DI X B: T O XI CI T Y G R A DI N G S C A L E  ................................................................5 8  
R E F E R E N C E S  .......................................................................................................................5 9  
 
 

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 1 7  of 6 1  
LI S T O F A B B R E VI A TI O N S  
 
A E  
A d verse E ve nt  
B L A  
Bi ol o gics Lice nse A p plicati o n  
C F U  
C ol o n y F or mi n g U nit  
CI  
C o nfi de n ce I nter val  
C R F  
Case Re p ort F or m  
C T  
C h olera T o xi n  
C V D  
Ce nter f or Vacci ne De v el o p me nt  
D M P  
Data Ma na ge me nt P la n 
e C R F  
electr o nic Case Re p ort F or m  
E D C  
Electr o nic Data C a pt ure 
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 FI  
Ge o metric Mea n F ol d I ncrease  
G M T  
Ge o metric Mea n T iter 
I B C 
I nstit uti o nal Bi osafet y C o m mittee 
I C F 
I nf or me d C o nse nt For m  
I C H 
I nter nati o nal C o nfere n ce o n Har m o nizati o n 
I N D 
I n vesti gati o nal Ne w Dr u g A p plicati o n  
I P D 
I m p orta nt Pr ot oc ol De viati o ns 
I R B 
I nstit uti o nal Re vie w B oar d 
L P S  
li p o p ol ysacc hari de 
S A E  
Seri o us A d verse E ve nt  
S A P  
Statistical A nal ysis Pla n  
S M C  
Safet y M o nit ori n g C o m mittee  
S M M  
S p o ns or Me dical M o nit or  
S M P  
Safet y Ma na g e me nt Pla n  
S V A  
Ser u m Vi bri oci dal A nti b o d y  
T M F  
Trial Master File  
U S  
U nite d States  
V A X C H O R A  
V A X C H O R A ( C h olera Vacci ne, Li ve, Oral)  
V. c h oler ae  
Vi bri o c h oler ae  
W H O  
W orl d Healt h Or ga nizati o n  
 

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 1 8  of 6 1  
1  
I N T R O D U C TI O N  
1. 1  
B ac k gr o u n d  
C h olera is a n ac ute e nteric i nfecti o n ca use d b y t he bacteri u m V. c h oler a e O 1 or O 1 3 9 a n d is 
tra ns mitte d b y t he i n gesti o n of water or f o o d c o ntai ni n g t he or ga nis m. T he ill ness pri nci pall y 
occ urs i n c o u ntries wit h i ns ufficie nt access t o safe wat er a n d pr o per  sa nitati o n, wit h e ve n m ore 
dra matic i m pact i n areas w here basic e n vir o n me ntal i nfrastr uct ur es are disr u pte d or ha v e bee n 
destr o ye d.  
C h olera is c haracterize d i n its m ost se vere f or m (c h olera gra vis) b y a s u d de n o nset of ac ute 
electr ol yte-ric h water y diarr hea t hat ca n lea d t o se vere de h y drati o n a n d deat h. T he e xtre mel y s h ort 
i nc u bati o n peri o d— a p pr o xi matel y 1 2 h o urs t o 5 d a ys — e n ha nces t he p ote ntiall y e x pl osi ve patter n 
of o ut brea ks, as t he n u m ber of cases ca n rise v er y q uic kl y.  
C h olera re mai ns a n i m p orta nt p u b lic healt h c o ncer n wit h f oc us o n de vel o pi n g c o u ntries. I n 2 0 1 4, 
a t otal of 1 9 0, 5 4 9 c h olera cases wit h 2, 2 3 1 deat hs were re p orte d t o W H O b y 4 2 c o u ntries res ulti n g 
i n a n o verall cas e fatalit y rate ( C F R) of 1. 1 7 %. C o m pare d t o 2 0 1 3, t his re prese nts a 4 7 % i ncrease  
(W H O 2 0 1 5 ). Deat hs d ue t o c h olera were re p orte d b y 2 4 c o u nties; 1 8 8 2 deat hs occ ur re d i n Africa, 
4 2 i n Asia, a n d 3 0 7 i n His pa ni ola. I m p orte d cases were re p orte d fr o m 1 1 c o u ntries i ncl u di n g t he 
U S A  a n d Ca na d a i n 2 0 1 4.  It is esti mate d t hat 1. 3 -4. 0 milli o n c h olera cases, wit h 2 1, 0 0 0 -1 4 3, 0 0 0 
deat hs, occ ur eac h year w orl d wi de  (Ali 2 0 1 5 ).  U n der-re p orti n g is ofte n d ue t o fear of ne gati ve 
i m pact o n tra vel a n d tra de i n t he affecte d area  a n d li mitati o ns i n s ur veilla nce s yste ms, 
i nc o nsiste ncies i n case d efi niti o ns a n d lac k of la b orat or y dia g n ostic ca p acities. T he persiste nce of 
c h olera i n ma n y c o u ntries i n Asia a n d Africa, t he a p peara n ce of p artic ularl y se vere cli nical dis ease  
d ue t o El T or str ai ns e x pressi n g classical bi ot y pe c h olera t o xi n, a n d t he i n creasi n g pre v ale nce of 
a nti micr o bial resista n ce ma ke t he c o ntr ol of c h olera a hi g h pri orit y o n t he p u blic healt h a ge n d a. 
T w o W H O pre q ualifie d Oral C h olera Vacci nes ( O C Vs) are c urr e ntl y a v aila ble o n t he i nter nati o nal 
mar ket ( D u k oral ®  [ Cr ucell; Lei de n, T he Net herla n ds]  a n d S ha n c h ol  [ S ha nt ha Bi otec h nics; 
H y dera b a d, I n dia]) ) f or i n di vi d uals a ge d ≥ 1 year a n d ol der.  
T he  V. c h oler ae, str ai n C V D 1 0 3-H g R was de v el o pe d as a li ve, oral vacc i n e f or t he pre ve nti o n of 
c h olera i n a d ults, a n d  li ce nse d i n se v eral c o u ntries e x-U S u n der t he tra de na mes Or o c h ol a n d 
M utac h ol .  Cli nical trial e x perie nce wit h  C V D 1 0 3 -H g R i ncl u des a d mi nistrati o n t o m ore t ha n 
2 7, 0 0 0 a d ults a n d c hil d re n as y o u n g as 3 m o nt hs ol d, a n d o v er 5 0 0, 0 0 0 c o m merci al d oses of 
C V D  1 0 3 -H g R vacci ne  were  s ol d wit h a n i n dicati o n i n tra velers t w o years or ol der.  
T he sa me strai n was re d e vel o pe d b y Pa x Va x a n d is n o w lice nse d f or use u n der t he tra d e na m e 
V A X C H O R A ®  ( B L A S T N 1 2 5 5 9 7/ 0). I n J u ne 2 0 1 6 V A X C H O R A  was a p pr o ve d b y t he F D A  f or 
use i n a d ults 1 8 t hr o u g h 6 4 years of a ge tr a velli n g t o c h olera -affecte d area s. 
St u dies  i n c hil dre n i n b ot h de vel o pe d a n d de vel o pi n g c o u ntries usi n g  a si n gle d ose of  t he 
C V D  1 0 3 -H g R vacc i ne strai n s h o we d t he vacci ne was well t olerat e d a n d s u g geste d t hat t he 
i m m u ne res p o nse (meas ure d b y vi bri oci dal ser oc o n versi o n rate a n d G M T) t o a si n gle d ose of 
vacci ne was l o wer t ha n t he res p o nses i n a d ults.   

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 1 9  of 6 1  
T a ble 1 : Or oc h ol Pe di at ric Tri als 
C o u ntr y  
A ge  
D ose ( C F U)  
N  
Refere nce  
I n d o nesia 
5 t o 9 y  
U p t o 1 x 1 0 1 0 
4 1 2  
S u har y o n o 1 9 9 2  
I n d o nesia 
2 t o 5 y  
5 x 1 0 9 
~ 1 5 0  
Si ma nj u nta k 1 9 9 3  
C hile  
5 t o 9 y  
5 x 1 0 9 
1 7 8  
La g os 1 9 9 5  
C hile  
2 t o 4 y  
5 x 1 0 9 
1 0 0  
La g os 1 9 9 6  
C hile  
3 t o 1 7 m o  
5 x 1 0 9 
3 1 2  
La g os 1 9 9 9a  
A ustria  
6 m o t o 1 2 y  
5 x 1 0 8 
2 9  
Wie der ma n n 1 9 9 8  
I n d o nesia 
2 t o 1 8 y  
5 x 1 0 9 
> 1 5, 0 0 0  
Ric hie 2 0 0 0  
Ec u a d or  
6 t o 1 3 y  
5 x 1 0 8 
1 3 9  
C o o per 2 0 0 0  
Ga b o n  
4 t o 1 6 y  
5 x 1 0 9 
2 7 5  
Fa uc h er 2 0 0 2  
I n 3 4 9 h ealt h y 5-9 year ol d C hilea n c hil dre n g i v e n 5 x 1 09 C F U of C V D 1 0 3 -H g R ( n = 1 7 8) or 
place b o ( n = 1 7 1), t he v acci ne  was well t olerat e d a n d n o ne of t he a d verse e ve nts o cc urre d at a 
si g nifica ntl y greater rate t ha n i n t he place b o gr o u p ( C V D 3 1 0 0 2, La g os 1 9 9 5 ). I n a n e ns ui n g p hase, 
t he a ge of t he st u d y s u bjects was l o were d t o 2-4 years ( C V D 3 1 0 0 3, La g os 1 9 9 6 ). I n a d o u ble-
bli n d ra n d o mize d st u d y, 1 0 0 c hil dre n recei v e d a si n gle d ose of C V D 1 0 3 -H g R c o ntai ni n g 
5 x  1 0 9 C F U a n d 1 0 0 paire d si bli n gs a d ose of place b o. A gai n, t h ere was n o si g nifica nt differe n ce 
bet wee n t he i n ci de nce of diarr hea or a n y ot her ad v erse e v e nts i n t he vacc i ne a n d place b o gr o u ps. 
Alt h o u g h Or oc h ol was use d i n c hil dre n i n E ur o pe, Ca na da, a n d A ustralia, t here are  n o p u blis he d 
st u dies of t he ser ol o gical res p o nse rates i n c hil dre n i n de vel o pe d c o u ntries. I m m u ne resp o ns es t o 
oral vacci nes ma y be ver y differe nt i n i nfa nts a n d c hil dre n i n e n de mic c o u ntries d ue t o e. g. nat ural 
e x p os ure t o i n fecti o ns, a ge-rel ate d differences i n i m m u ne f u ncti o n, brea st fee di n g a n d n utriti o nal 
stat us (Czer ki ns k y 2 0 1 5 , Sac k 2 0 0 8 ). T heref ore, t his st u d y is desi g ne d t o deter mi ne t he vi bri oci dal 
a nti b o d y res p o nse rates i n c hildre n i n de vel o pe d c o u ntries f oll o wi n g a si n gle d ose of  
V A X C H O R A .  
1. 1. 1  N a me a n d Descri pti o n of Acti ve V acci ne  
V A X C H O R A ® ™ ( C h olera Vacci ne, Li v e, Oral) is a li ve, atte n u ate d b acteri al vacci ne s us pe nsi o n 
f or oral a d mi nistrati o n i n dicate d f or acti ve i m m u nizati o n a gai nst disease ca us e d b y 
Vi bri o  c h oler ae ser o gr o u p O 1 i n a d ults 1 8 t hr o u g h 6 4 years of a ge tra veli n g t o c h olera -affecte d 
areas. It c o ntai ns t he V. c h oler ae strai n C V D 1 0 3-H g R. C V D 1 0 3 -H g R  was  c o nstr ucte d fr o m t he 
ser o gr o u p O 1 classic al I n a ba strai n 5 6 9 B b y deleti n g t he catal ytic d o mai n s e q ue nce of b ot h c o pies 
of t he ct x A ge n e, w hic h pre ve nts t he s y nt hesis of acti ve c h o lera t o xi n ( C T). T his atte n uate d strai n 
re mai ns a ble t o s y nt hesize t he i m m u n o ge nic n o n-t o xic B s u b u nit of C T (e nc o de d b y t he ctx B ge ne). 
I n a d diti o n, a mar ker was i nserte d i nt o t he h e m ol ysi n ge ne l oc us (hly A ) t o e na ble differe ntiati o n 
of t he vacci ne strai n  fr o m wil d t y pe V. c h oler ae O 1.  
Eac h d ose of V A X C H O R A is s u p plie d as a f oil pac ket of b uffer a n d a n acc o m pa n yi n g f oil pac ket 
of t he acti ve c o m p o n e nt (l y o p hilize d V. c h oler a e C V D 1 0 3 -H g R)  w hic h are rec o nstit ute d i n 
p urifie d b ottle d water t o f or m  a si n gle dose  acc or di n g t o t he i nstr ucti o ns i n Secti o n 4. 1 .  

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 2 0  of 6 1  
T he vacci ne str ai n is gr o w n i n fer m e nt ors u n der c o ntr olle d c o n diti o ns i n me di u m c o ntai ni n g 
casa mi n o aci ds, yeast e xtract, mi neral salts, a n d a n a nti -f oa mi n g a ge nt. T h e bacteria are c ollecte d 
b y filtrati o n, diafiltere d, a n d c o n ce ntr ate d b ef ore a d diti o n of a sta bilizati o n s ol uti o n c o ntai ni n g 
asc or bic aci d (a n a nti o xi da nt), H y -Case S F ( h y dr ol yze d cas ei n [a pr otei n deri ve d fr o m c o w’s 
mil k], a cr y o pr ote cta nt), s o di u m c hl ori de (a st a b ilizer), a n d s ucr ose (a cr y o pr ot ecta nt). T h e 
sta bilize d bacteria are l y o p hilize d, mille d, a n d ble n de d wit h drie d lact ose (a desicca nt a n d b ul ki n g 
a ge nt). T he acti ve c o m p o ne nt ble n d is fille d i nt o pac kets.  
T he b uffer c o m p o ne nt is ma n ufact ure d b y ble n di n g t o get her s o di u m bicar b o nate (a gastric aci d 
ne utralizer), s o di u m car b o nate (a b uffer), asc or bic aci d (a b uffer a n d water c hl ori ne ne utr alizer), 
a n d drie d l act ose (a ma n ufact uri n g fl o w ai d). T he b uffer c o m p o ne nt bl e n d is fille d i nt o pac k ets. 
O ne b uffer c o m p o n e nt p ac ket a n d o ne acti ve c o m p o ne nt pac k et are p ac ka g e d i nt o i n di vi d ual si n gle 
d ose cart o ns f or distri b uti o n.  
After rec o nstit uti o n, V A X C H O R A c o ntai ns 4 x 1 0 8 t o 2 x 1 09 c ol o n y f or mi n g u nits ( C F U) of li ve 
atte n uate d V. c h oler ae C V D 1 0 3 -H g R. T h e res ulti n g s us pe nsi o n s h o ul d be sli g htl y cl o u d y a n d 
ma y c o ntai n w hite partic ulates. T he acti ve a n d b uffer i n gr e die nts are s h o w n i n 
Ta ble 2  
(V A X C H O R A 2 0 1 6 ). 
T a ble 2 : V acci ne C o m p ositi o n  
I n gre die nt  
Q u a ntit y/ p ac ket   
Acti ve C o m p o ne nt P ac k et   
V. c h oler ae  C V D 1 0 3 -H g R  
4 x 1 0 8 t o 2 x 1 09 C F U  
S ucr ose  
≤ 1 6 5. 3 7 m g  
S o di u m c hl ori de  
≤ 1 7. 1 1 m g  
H y -Case S F ( h y dr ol yze d casei n)  
≤ 1 7. 1 1 m g  
Asc or bic aci d  
≤ 8. 5 5 m g  
Drie d lact ose   
≤ 2. 0 9 g  
B uffer C o m p o ne nt P ac k et  
S o di u m bicar b o nate  
2. 1 6 – 2. 4 1 g  
S o di u m car b o nate  
0. 2 4 -0. 4 9 g  
Asc or bic aci d  
1. 5 0 – 1. 8 0 g  
Drie d lact ose  
0. 1 8 – 0. 2 2 g  
C F U =c ol o n y f or mi n g u nits  
m g = milli gra ms  
g = gra ms  
 
1. 1. 2  S u m m ar y of Fi n di n gs fr o m N o ncli nic al St u dies  
V. c h oler a e  O 1  is a strictl y h u ma n pat h o ge n, he nce t here is n o vali d a ni mal m o del a vaila ble t o 
assess safet y or pre dict t he m uc osal i m m u ne res p o nse t o a li ve atte n uate d c h olera v acci ne  
(Ric har d s o n 1 9 9 4). C h olera bacilli will n ot c ol o nize or re plicat e i n healt h y a d ult a ni mals, t heref ore 
a ni mal st u dies w o ul d neit her be e x p ecte d t o i de ntif y p ote ntial t o xicit y fr o m t heir re plicati o n n or 
i m m u ne res p o nse t o t heir re plicati o n.  T he o nl y a ni mal m o dels of c h olera disease are ra b bits t hat 

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 2 1  of 6 1  
ha ve bee n s ur gicall y m o difie d usi n g li g ate d ileal l o o ps  (F or mal 1 9 6 1 ) or t h e Re m o va ble I ntesti nal 
Tie -A d ult Ra b bit ( RI T A R D) m o del  (Pierce 1 9 8 8 , Dziej ma n 2 0 0 5 , R ussell 1 9 9 2 , M orris 1 9 9 0 ), 
w hic h d o n ot pr o vi de a rele va nt m o del f or si n gle or re p eat d ose, carci n o ge nicit y or re pr o d ucti ve 
t o xic ol o g y st u dies of t his vacci ne. 
1. 1. 3  S u m m ar y of Fi n di n gs fr o m Cli nic al St u dies  
S a fet y  
T he safet y of V A X C H O R A was e val uate d i n f o ur ra n d o mize d, place b o -c o ntr olle d, m ultice nter 
cli nical trials. A t otal of 3 2 3 5 a d ults 1 8 t hr o u g h 6 4 years of a ge recei ve d o ne d ose of V A X C H O R A 
a n d 5 6 2 recei v e d place b o [ p h ysi ol o gic sali ne ( N = 5 5 1) or lact ose ( N = 1 1)]. O verall, t he mea n a g e 
was 3 2. 5 years; 5 3. 8 % of trial partici pa nts were fe male; 6 7. 1 % were W hite, 2 7. 3 % were Blac k or 
Africa n A merica n, 1. 8 % were Asia n, 1. 7 % were m ultiracial, 1. 3 % were ot her, 0. 6 % were 
A merica n I n dia n or Alas ka n Nati ve a n d 0. 3 % we re Nati ve Ha waiia n or Pacific Isla n der. T h ere 
were 9. 3 % His pa nic or L ati n o partici pa nts.  
A d ults 1 8 t hr o u g h 4 5 years of a ge recei ve d V A X C H O R A i n a m ulti -ce nter, d o u ble -bli n d, 
ra n d o mize d ( 8: 1), pl ace b o-c o ntr olle d tri al c o n d u cte d i n t he U nite d States a n d A ust ralia. T he safet y 
a nal ysis set i ncl u de d 2 7 8 9 V A X C H O R A reci pie nts. S olicite d a d verse reacti o ns were rec or de d 
dail y f or 7 da ys f oll o wi n g vacci nati o n. T he m ost c o m m o n a d verse reacti o ns (i nci de nce > 3 %) were 
tire d ness ( 3 1 %), h ea dac h e ( 2 9 %), a b d o mi nal pai n ( 1 9 %), na usea/ v o miti n g ( 1 8 %), lac k of a p p etite 
( 1 7 %) a n d diarr hea ( 4 %). 
I n a p o ole d a nal ysis of t he f o ur cli nical st u dies, 0. 6 % ( 2 0/ 3 2 3 5) of V A X C H O R A reci pie nts a n d 
0. 5 % ( 3/ 5 6 2) of place b o reci pie nts re p orte d a seri o us a d verse e v e nt wit hi n 6 m o nt hs p ost -
vacci n ati o n. N o ne of t hese e ve nts were c o nsi dere d t o be relate d t o vacci nati o n. Refer t o t he 
V A X C H O R A pac ka g e i nsert f or 
a c o m plete s u m mar y of fi n di n gs fr o m cli nical st u dies 
(V A X C H O R A 2 0 1 6 ). 
Pr otecti ve Effi c ac y  
I n a ra n d o mize d, d o u ble-bli n d, sali ne place b o -c o ntr olle d V. c h oler ae  c h alle n ge st u d y c o n d ucte d 
i n t he U S, s u bjects 1 8 t hr o u g h 4 5 years of a ge ( N = 1 9 7) wit h n o pri or hist or y of c h olera i nfecti o n 
or tra v el t o a c h olera -e n de mic area i n t he pre vi o us 5 years were ra n d o mize d acc or di n g t o a 1: 1 
rati o t o recei ve o ne d ose of V A X C H O RA or place b o. T he c halle n ges were s plit i nt o 2 c o h orts f or 
1 0 da y a n d 3 m o nt h c halle n ges. S u bjects were a d mitte d t o a n i n patie nt u nit. T he oral c halle n ge 
c o nsiste d of 1 x 1 0 5 C F U li ve wil d t y pe V. c h oler ae  El T or I na ba N 1 6 9 6 1 i n 3 0 m L Na H C O 3 
b uffer at 1 0 d a ys or 3 m o nt hs p ost -vacci nati o n. T h e c o -pri mar y o bjecti ves were t o de m o nstrate t he 
effic ac y of a si n gle d os e of V A X C H O R A i n t he pre v e nti o n of m o d erate t o se v ere diarr hea 
f oll o wi n g c halle n ge at 1 0 da ys a n d 3 m o nt hs p ost-vacci nati o n. M o derate t o se vere diar r hea was 
defi ne d as c u m ulati ve diarr heal p ur ge ≥ 3 liters ( L) wit hi n 1 0 da ys after c halle n ge. Diarr h eal st o ol 
was defi ne d as ≥ 2 u nf or me d st o ols (ta kes s ha pe of c o ntai ner) c ollecte d d uri n g a 4 8 h o ur peri o d 
wei g hi n g ≥ 2 0 0 gra ms ( g) or a si n gle u nf or me d st o o l ≥ 3 0 0 g. V A X C H O R A reci pie nts c halle n g e d 
at 1 0 da ys p ost -vacci nati o n a n d V A X C H O R A reci pie nts c halle n ge d at 3 m o nt hs p ost -vacci nati o n 
were c o m pare d wit h a p o ole d gr o u p of place b o (sali ne) reci pie nts c halle n ge d at 1 0 da ys or 
3  m o nt hs p ost -vacci nati o n.  

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 2 2  of 6 1  
Of t h e 9 5 V A X C H O R A reci pie nts, 6 8 were c halle n ge d; 3 5 were c halle n ge d at 1 0 da ys p ost -
vacci nati o n a n d 3 3 w ere c halle n ge d at 3 m o nt hs p ost -vacci nati o n. Of t he 1 0 2 place b o reci pie nts, 
6 6 were c halle n ge d; 3 3 were c halle n ge d at 1 0 d a ys p ost -vacci nati o n a n d 3 3 at 3 m o nt hs p ost -
vacci nati o n. Vacci ne efficac y a g ai nst t he occ urre nce of m o derate t o se vere diarr hea at 1 0 da ys 
p ost -vacci nati o n w as 9 0. 3 % [ 9 5 % CI 6 2. 7 %, 1 0 0. 0 %] a n d at 3 m o nt hs p ost -vacci nati o n was 7 9. 5 % 
[ 9 5 % CI 4 9. 9 %, 1 0 0. 0 %] 
I m m u n o ge nicit y  
A vi bri oci dal a nt i b o d y assa y was use d t o meas ure ser u m le vels of ne utralizi n g a nti b o dies a gai nst 
t he vacci ne strai n. I n t he s u bset of s u bjects c h alle n ge d i n t he c h olera c hall e n ge st u d y, 9 1 % [ 9 5 % 
CI 8 2 %, 9 7 %] of vacci ne es ser oc o n v erte d pri or t o c halle n ge a n d 9 % de vel o pe d m o derate t o se v ere 
c h olera f oll o wi n g c h alle n ge, w hile 2 % of place b o reci pie nts ser oc o n v erte d pri or t o c halle n ge a n d 
5 9 % de vel o pe d m o derat e t o se vere c h olera f oll o wi n g c halle n ge. ( Ser oc o n versi o n was defi ne d as 
a ≥ 4-f ol d rise i n ser u m vi bri oci dal a nti b o d y fr om baseli ne t o 1 0 da ys p ost -vacci nati o n.) Bas e d o n 
t he o bser ve d ass ociati o n bet wee n s er oc o n v ersi o n a n d pr otecti o n fr o m V. c h oler ae  diseas e,  
ser oc o n versi o n rate at 1 0 da ys p ost-vacci nati o n was use d t o e val uate res p o nse t o vacci nati o n i n 
ot her a ge co h orts .  
I n a ra n d o mize d, d o u bl e-bli n d, sali ne place b o -c o ntr olle d safet y a n d i m m u n o ge nicit y st u d y 
c o n d ucte d i n t he U S a n d A ustralia, a t otal of 3 1 4 6 s u bjects 1 8 t hr o u g h 4 5 years of a ge n ot 
pre vi o usl y e x p ose d t o c h olera were ra n d o mize d 8: 1 t o recei ve o ne d os e of V A X C H O R A or 
place b o. I n t his st u d y, t he rates of ser oc o n versi o n were 9 3. 5 % [ 9 5 % CI 9 2. 5 %, 9 4. 4 %] i n vacci ne 
reci pie nts a n d 4 % [ 9 5 % CI 2 %, 7 %] i n place b o reci pie nts at 1 0 da ys p ost-v acci nati o n.  
I n a ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d safet y a n d i m m u n o ge nicit y st u d y c o n d ucte d i n 
t he U S, a t otal of 3 9 8 s u bjects 4 6 t hr o u g h 6 4 years of a ge wit h n o pri or hist or y of c h olera i nf ecti o n 
or tra vel t o a c h olera e n de mic area i n t he pre vi o us 5 years were ra n d o mi ze d 3: 1 t o recei ve o n e 
d ose of V A X C H O R A or place b o.  
Ser oc o n versi o n rates at 1 0 da ys p ost -v acci nati o n b y classical I na b a vi bri oci dal a nti b o d y a m o n g 4 6 
t hr o u g h 6 4 year ol d s u bjects were c o m p are d t o t h ose i n 1 8 t hr o u g h 4 5 year ol d s u bjects.  A d ults 
4 6 t hr o u g h 6 4 years were s h o w n t o ha ve a n o n -i nferi or rat e of ser oc o n versi o n b y classical I na ba 
vi bri oci dal a nti b o d y at 1 0 da ys p ost vacci nati o n  c o m pare d t o a d ults 1 8 t hr o u g h 4 5 years of a ge. 
Refer t o t he V A X C H O R A pac k a ge i ns ert f or a c o m plete s u m ma r y of fi n di n gs fr o m cli nical st u dies 
(V A X C H O R A 2 0 1 6 ). 
1. 2  
R ati o n ale  f or t he C urre nt St u d y 
1. 2. 1  R ati o n ale f or D os a ge  a n d R o ute of A d mi nistr ati o n  
V A X C H O R A is a n orall y a d mi nistere d v acci ne t hat is pre p are d a n d a d mi nistere d i n a h ealt hcare 
setti n g. Eac h d ose of V A X C H O R A is s u p plie d as a f oil pac k et of b uffer a n d a n acc o m pa n yi n g f oil 
pac ket of t he acti ve c o m p o ne nt (l y o p hilize d V. c h oler ae C V D 1 0 3 -H g R)  w hic h are rec o nstit ute d 
i n p urifie d b ottle d water t o f or m a si n gle d ose .  Eac h vacci ne pac ket c o ntai ns 4 x 1 0 8 t o 2 x 1 09 
C F U of li ve atte n uate d V. c h oler ae . Refer t o Secti o n 4. 1  f or rec o nstit uti o n a n d a d mi nistrati o n 
i nstr ucti o ns.  

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 2 3  of 6 1  
1. 2. 2  R ati o n ale f or Pe di atri c St u d y  
Pre vi o us pe diatric cli ni cal trial e x p erie nce wit h C V D 1 0 3 -H g R i n v ol ve d t he Or o c h ol E ®  
f or m ulati o n t hat c o ntai n e d a p pr o xi matel y 5 x 1 09  C F U/ d ose. A si n gle d ose of Or oc h ol E elicite d  
hi g h rates of ser oc o n versi o n i n s u bjects wit h l o w or a bse nt baseli ne titers of vi bri oci dal  a nti b o d y, 
wit h a safet y pr ofile si milar t o t hat o bs er ve d i n a d ults  (Or oc h ol p ac k a ge i nsert 2 0 0 0 ). I n areas 
w here c h olera was e n de mic or w here o ut brea ks ha d occ urre d, c hil dre n w h o di d n ot ser oc o n vert 
alrea d y h a d ele v ate d  bas eli ne vi bri oci dal titers. T hese pe diatric st u dies wit h Or oc h ol E were 
acce pte d b y re g ulat or y a ge ncies i n t he lice ns ure of C V D 1 0 3 -H g R i n t he pe diatric p o p ulati o n 
2  years of a ge a n d hi g her.  
C o m pare d wit h ol der c hil dre n, y o u n ger c hil dre n h a ve si milar rates of s er u m vi bri oci dal a nti b o d y 
ser oc o n versi o n b ut l o wer GM Ts, as d e m o nstrate d i n I n d o n esia  (Si ma nj u nta k  1 9 9 3 , La g os 1 9 9 9 a ) 
a n d C hile (La g os 1 9 9 9 a). Si nce t hese cli nical trials were carrie d o ut i n eit her de vel o pi n g c o u ntries 
or i n s u b -p o p ulati o ns i n tra nsiti o nal c o u ntries, ma n y fact ors ca n c o ntri b ute t o t he differe nce, 
i ncl u di n g s oci oec o n o mic stat us, e n vir o n me ntal e nter o pat h y ( meas ure d as s mall b o wel bacteri al 
o ver gr o wt h , L a g os 1 9 9 9 b ), ge o hel mi nt hs a n d earl y H.  pyl ori gastritis  (Le vi ne 2 0 1 0 ).  
Si nce t hese fact ors w o ul d li kel y n ot be prese nt i n t he U S a n d ot her d e v el o pe d c o u ntries, it is 
p ossi ble t hat c hil dre n fr o m t hese c o u ntries ma y m o u nt m ore s u bsta ntial i m m u ne res p o ns es t o 
V A X C H O R A. T his trial re pres e nts t he first e val u ati o n of t he i m m u n o ge ni cit y of a n y f or m ulati o n 
of C V D 1 0 3 -H g R i n s uc h c hil dre n. T his tri al is d esi g ne d t o e n a ble t he i n de pe n de nt e val uati o n of 
t he i m m u n o ge nicit y of V A X C H O R A i n se parate a ge c o h orts: 1 2 t o < 1 8 years, 6 t o < 1 2 y ears, a n d 
2 t o < 6 years.  
2  
O B J E C TI V E S A N D E N D P OI N T S  
2. 1  
I m m u n o ge nicit y O bjecti ves a n d E n d p oi nts  
1)  C o h ort 1: 1 2 t o < 1 8 y e a rs  
Pri m ar y I m m u n o ge nicit y O bjecti ves : 
•  De m o nstrate t hat t he ser oc o n versi o n rate at Da y 1 1 i n pe diatric s u bjects is n o n -i nferi or t o 
t he ser oc o n v ersi o n rate at Da y 1 1 i n a d ults bet wee n t he a ges of 1 8 a n d 4 5 y ears. 
•  De m o nstrate t hat t he ser oc o n versi o n rate i n pe di atric s u bjects is greater t ha n or e q u al t o 
7 0 % wit h 9 8. 3 % c o nfi de nce.  
Pri m ar y E n d p oi nt:  
•  T he pr o p orti o n of s u bjects ac hie vi n g ser oc o n versi o n of ser u m vi bri oci dal a nti b o d y ( S V A) 
a gai nst t he cl assical I n a ba bi ot y pe of V. c h oler ae  at Da y 1 1 f oll o wi n g o ne d ose of 
V A X C H O R A, defi n e d as a 4 -f ol d or greater rise o ver bas eli ne Da y 1 S V A titer.  T his 
pr o p orti o n of ser oc o n vert ers is calle d t he s er oc o n v ersi o n rate.  
Sec o n d ar y E n d p oi nts:  
•  S er oc o n versi o n  of  S V A  a gai nst t he classical I na b a bi ot y pe of V . ch oler a e at Da y s 2 9 , 9 1 
a n d 1 8 1 f or all s u bjects. 
•  S er oc o n versi o n  of  S V A a gai nst t he classical I na b a bi ot y pe of V . ch oler a e at Da ys 3 6 5, 5 4 7 
a n d 7 3 0 f or vacci ne es partici pati n g i n t he s u b -st u d y. 
E x pl or at or y O bjecti ve :  
•  E x pl ore me m or y B cell res p o nse t o V A X C H O R A vacci nati o n at eac h ti me p oi nt.  
 

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 2 4  of 6 1  
E x pl or at or y E n d p oi nt:  
•  Ass ociate d me m or y B cell e n d p oi nts:  A nti – O 1 li p o p ol ysacc hari de ( L P S) me m or y B cell 
c o nce ntr ati o n at Da ys 1, 9 1, 1 8 1 f or t he s u bjects i n t he acti ve treat me nt gr o u p a n d t he 
place b o cr oss o v er g r o u p a n d Da ys 3 6 5, 5 4 7, 7 3 0 f or t he s u bjects i n t he acti ve treat me nt 
gr o u p  w h o partici pat e i n t he s u b -st u d y. 
 
2)  C o h ort 2: 6 t o < 1 2 ye ars  
Pri m ar y I m m u n o ge nicit y O bjecti ves : 
•  De m o nstrate t hat t he ser oc o n versi o n rate at Da y 1 1 i n pe diatric s u bjects is n o n -i nferior t o 
t he ser oc o n v ersi o n rate at Da y 1 1 i n a d ults bet wee n t he a ges of 1 8 a n d 4 5 y ears. 
•  De m o nstrate t hat t he ser oc o n versi o n rate i n pe di atric s u bjects is greater t ha n or e q u al t o 
7 0 % wit h 9 8. 3 % c o nfi de nce.  
Pri m ar y E n d p oi nt:  
•  T he pr o p orti o n of s u bjects ac hie vi n g ser oc o n versi o n of ser u m vi bri oci dal a nti b o d y ( S V A) 
a gai nst t he cl assical I n a ba bi ot y pe of V. c h oler ae  at Da y 1 1 f oll o wi n g o ne d ose of 
V A X C H O R A, defi n e d as a 4 -f ol d or greater rise o ver baseli ne Da y 1 S V A titer.  
Sec o n d ar y E n d p oi nt:   
•  S er oc o n versi o n  of ser u m vi bri oci dal a nti b o d y ( S V A) a gai nst t he classical I na ba  bi ot y pe of  
V. c h oler ae at D a y 2 9 f oll o wi n g o ne d o se of V A X C H O R A.  
 
3)  C o h ort 3: 2  t o < 6 ye ars 
Pri m ar y I m m u n o ge nicit y O bjecti ves  
•  De m o nstrate t hat t he ser oc o n versi o n rate at Da y 1 1 i n pe diatric s u bjects is n o n-i nferi or t o 
t he ser oc o n v ersi o n rate at Da y 1 1 i n a d ults bet wee n t he a ges of 1 8 a n d 4 5 y ears. 
•  De m o nstrate t hat t he ser oc o n versi o n rate i n pe di atric s u bjects is greater t ha n or e q u al t o 
7 0 % wit h 9 8. 3 % c o nfi de nce.  
Pri m ar y E n d p oi nt:  
•  T he pr o p orti o n of s u bjects ac hie vi n g ser oc o n versi o n of ser u m vi bri oci dal a nti b o d y ( S V A) 
a gai nst t he cl assical I n a ba bi ot y pe of V. c h oler ae  at Da y 1 1 f oll o wi n g o ne d ose of 
V A X C H O R A , defi n e d as a 4 -f ol d or greater rise o ver baseli ne Da y 1 S V A titer.  
Sec o n d ar y E n d p oi nt:  
•   Ser oc o n versi o n of s er u m vi bri oci dal a nti b o d y ( S V A) a gai nst t he classical I n a ba bi ot y pe 
of V. c h oler ae  at Da y 2 9 f oll o wi n g o ne d o se of V A X C H O R A.  
 
2. 2  
S afet y O bjecti v e  a n d E n d p oi nts  
O bjecti ve : 
•  E val uate t he safet y a n d cli nical acce pt a bilit y of V A XC H O R A i n chil dre n . 
E n d p oi nts : 
E val uate t he safet y a n d t olera bilit y of V A X C H O R A usi n g t he f oll o wi n g e n d p oi nts:  
•  S olicite d a d verse e ve nts t hr o u g h  Da y 8 : a b d o mi nal pai n, hea dac h e, lac k of a p p etite, 
tire d ness, diarr hea, na us ea, v o miti n g a n d fe ver, b y a ge c o h ort a n d o verall  
•  U ns olicite d a d verse e ve nts t hr o u g h Da y 2 9 , b y a g e c o h ort a n d o v erall 
•  Seri o us a d verse e ve nts t hr o u g h Da y 1 8 1, b y a g e c o h ort a n d o verall . 

V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 2 5  of 6 1  
2. 3  
Acce pt a bilit y  
O bjecti ve:  
•  E val uate t he acce pta bilit y of V A X C H O R A  usi n g t he f oll o wi n g e n d p oi nt . 
E n d p oi nt:  
•  T he perce nt of s u bje cts i n eac h a ge c o h ort a ble t o c o m ple te d osi n g acc or di n g t o pr ot oc ol. 
2. 4  
P al at a bilit y  
O bjecti ve:   
•  E val uate t he pal ata bilit y of V A X C H O R A  usi n g t h e f oll o wi n g e n d p oi nts . 
E n d p oi nts : 
•  Palata bilit y of vacci ne assesse d b y t he s u bject usi n g a 5 -p oi nt He d o nic s cale i n C o h orts 1 
a n d 2. 
•  Palata bilit y of vacci ne assesse d b y t he care gi ver usi n g a 5 -p oi nt He d o nic s cale i n C o h ort 
3.  
 
3  
S T U D Y P L A N  
3. 1  
St u d y Desi g n  
T his is a ra n d o mize d, place b o -c o ntr olle d, d o u bl e -bli n d, si n gle -cr oss o ver st u d y wit h t hree a ge 
c o h orts a n d t w o treat me nt gr o u ps wit hi n eac h c o h ort  e nr olle d c o n c urre ntl y  (F i g ure 1 ). 
F i g ure 1 .  P X V X -V C -2 0 0 -0 0 6  St u d y Desi g n  
 
 
 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 2 7  of 6 1  
3. 2  
N u m ber of St u d y P artici p a nts  
U p t o 5 9 5  healt h y c hil dre n a ges 2  years t o < 1 8 years of a ge will be e nr olle d b y a ge c o h ort  as 
f oll o ws: 
•  C o h ort 1:  1 2 t o < 1 8  years ( n = 1 5 0 : acti ve treat me nt gr o u p, n = 2 5: place b o cr oss o ver gr o u p 
f or 1 7 5 t otal s u bjects ) 
•  C o h ort 2:  6 t o < 1 2  y ears ( n = 1 5 0 : acti ve treat me nt gr o u p, n = 2 5: place b o cr oss o ver gr o u p 
f or 1 7 5 t otal s u bjects ) 
•  C o h ort 3:  2 t o < 6  years ( n = 2 1 0 : acti ve treat me nt gr o u p, n =3 5 : place b o cr oss o ver gr o u p 
f or 2 4 5 t otal s u bjects ) 
C o h orts ma y be e nr olle d c o nc urre ntl y.  
3. 3  
Esti m ate d St u d y D ur ati o n  
T he mai n st u d y c o nsists of a scree ni n g peri o d of 3 0 da ys, Da y 1 vacci nati o n , a n o bser vati o n peri o d 
fr o m Da y 1 t o Da y 2 9, a n d a f oll o w-u p peri o d t hr o u g h Da y 1 8 1. Place b o cr oss o ver has a n o pti o nal 
acti ve vacci nati o n at Da y 1 8 1 after u n bli n di n g, wit h a 6 m o nt h of p ost vacci nati o n f oll o w -u p peri o d  
(t o Da y 3 6 5). C o h ort 1 has a n o pti o nal  s u b-st u d y c o nsisti n g of a l o n g-ter m f oll o w-u p peri o d 
t hr o u g h Da y 7 3 0.   
3. 4  
St u d y P o p ul ati o n  
3. 4. 1  I ncl usi o n Criteri a 
S u bjects m ust meet all of t he f oll o wi n g criteria i n or der t o be e nr olle d:  
1.  Male or fe m ale . 
2.  Bet wee n 2 a n d < 1 8 years of a ge o n Da y 1.  
3.  I n g e neral g o o d healt h.  
4.  A ble a n d willi n g t o pr o vi de i nf or me d ass e nt f or st u d y partici pati o n.  
5.  Pri mar y care gi ver is a ble a n d willi n g t o pr o vi de i nf or me d c o nse nt f or st u d y partici pati o n.  
6.  (f or fe males of c hil d beari n g p ote ntial) Usi n g a n acce pta ble met h o d of c o ntrace pti o n 
t hr o u g h Da y 2 9  (see Secti o n 5. 9 ). 
3. 4. 2  E xcl usi o n Criteri a  
S u bjects w h o meet a n y of t he f oll o wi n g criteri a ca n n ot be e nr olle d:  
 
1.  C urre nt ac ute g astr oi ntesti nal ill ness  or l o ose st o ols wit hi n 3 da ys of Da y 1 visit . 
2.  C urre nt ac ute fe brile ill n ess.  
3.  Hist or y of c h olera i nfecti o n.  
4.  Hist or y of c h olera vacci n ati o n.  
5.  Hist or y of se vere aller gi c reacti o n (e. g. a n a p h yla xis) t o a n y i n gre die nt of  V A X C H O R A . 
6.  C o n ge nital or ac q uire d i m m u n o defic ie nc y. 
7.  (f or fe males of c hil d beari n g p ote ntial) Pre g na nt 
8.  A n y ot her c o n diti o n t hat, i n t he o pi ni o n of t he I n v esti gat or, creates a n u nacce pta ble ris k t o 
t he s u bject. 
9.  A n y ot her c o n diti o n t hat, i n t he o pi ni o n of  t he I n vesti gat or, will i nterfere wi t h t he c o n d uct 
of t he st u d y or t he vali dit y of t he data.  

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 2 8  of 6 1  
1 0.  D urati o n of > 2 wee ks of a b n or mal st o ol patter n , defi ne d as < 3 st o ols per wee k or > 2 st o ols 
per da y i n t he past 6 m o nt hs .  
1 1.  Re g ular use of la x ati ves i n t he past 6 m o nt hs.  
1 2.  Hist or y of e nter ot o xi ge ni c E. c oli  i nfecti o n. 
1 3.  Tra vel t o c h olera -e n de mi c area i n t he pre vi o us 5 years.  
1 4.  N ursi n g/ breastf ee di n g.  
1 5.  Recei ve d or pla ns t o recei ve t he f oll o wi n g fr o m 1 4 da ys pri or t o t he st u d y vacci n ati o n 
t hr o u g h 1 1 da ys after vacci nati o n: 
A n y ot her  lice nse d v acci nes  
A nti bi otics or c hl or o q ui ne  or a n y ot her i n vesti gati o nal a ge nts . 
1 6.  Recei ve d or pla ns t o recei ve a n y ot h er i n vesti gati o nal a ge nt t hr o u g h o ut t he mai n st u d y 
( Da y 1 8 1). 
 
4  
S T U D Y V A C CI N E  
4. 1  
V A X C H O R A  
V A X C H O R A ( C h olera Vacci n e, Li ve, Oral) is a li ve, atte n uate d bacterial vacci ne s us pe nsi o n f or 
oral a d mi nistrati o n i n dicate d f or acti ve i m m u nizati o n a gai nst disease ca us e d b y Vi bri o c h oler ae 
ser o gr o u p O 1 i n a d ults 1 8 t hr o u g h 6 4 years of a g e tra v eli n g t o c h olera -affecte d areas. It c o ntai ns 
t he V. c h ol er ae str ai n C V D 1 0 3-H g R. C V D 1 0 3 -H g R, c o nstr ucte d fr o m t he ser o gr o u p O 1 classical 
I n a ba strai n 5 6 9 B b y deleti n g t he catal ytic d o mai n se q ue nce of bot h c o pies of t he ctx A ge ne, w hic h 
pre ve nts t he s y nt hesis of acti ve c h olera t o xi n ( C T). T his atte n uate d strai n re mai ns a ble t o 
s y nt hesize t he i m m u n o ge nic n o n-t o xic B s u b u nit of C T (e nc o d e d b y t he ctx B ge ne). I n a d diti o n, a 
mar ker w as i nserte d i nt o t he he m o l ysi n ge ne l oc us (hly A ) t o e n a ble differe ntiati o n of t he vacci n e 
strai n fr o m wil d t y pe V. c h oler ae O 1.  
Eac h d ose of V A X C H O R A is s u p plie d as a f oil pac ket of b uffer a n d a n acc o m pa n yi n g f oil pac ket 
of t he acti ve c o m p o n e nt (l y o p hilize d V. c h oler a e C V D 1 0 3 -H g R)  w hic h are rec o nstit ute d i n 
p urifie d b ottle d w ater t o f or m  a si n gle d ose .  T he res ulta nt s us pe nsi o n is a d mi nistere d at a d ose of 
a p pr o xi matel y 4 x 1 0 8 t o 2 x 1 0 9 c olo n y f or mi n g u nits ( C F U) . S u bjects will ta ke n ot hi n g b y m o ut h 
(f o o d a n d w ater) f or 6 0  mi n u tes bef ore a n d after vacci nati o n.  
Refer t o t he c urre nt versi o n of t he P X V X -V C -2 0 0 -0 0 6  P har mac y M a n ual f or detaile d pre parati o n, 
rec o nstit uti o n, a d mi nistrati o n a n d st ora ge of t he st u d y vacci ne.  
F or S u bjects a ge d 6 ye a rs a n d ol der ( C o h ort 1 a n d 2) :  
Rec o nstit uti o n s h o ul d be c o m plete d wit hi n 1 5 mi n utes of re m o vi n g t he cart o n fr o m t h e freezer. 
V A X C H O R A will be pre pare d b y s us p e n di n g t he c o nte nts of t he b uffer sac het i nt o a n o pa q u e 
c o ntai ner c o ntai ni n g 1 0 0  m L p urifie d b ottle d water  pr o vi de d b y Pa x Va x , a nd stirri n g t he fi nal 
s us pe nsi o n f or at least 3 0 sec o n ds. V A X C H O R A m ust be c o ns u me d wit hi n 1 5 mi n utes of 
rec o nstit uti o n. T he s u bject s h o ul d dri n k t he f ull c o nte nts of t he c u p at o nce.  
F or S u bjects y o u n ger t h a n 6 ye ars  ( C o h ort 3 ):  
Vacci n e will be pre pare d b y s us pe n di n g t he c o nte nts of t he b uffer sac h et i nt o  a n o pa q ue c o ntai ner 
c o ntai ni n g 1 0 0 m L of p urifie d b ottle d water  pr o vi de d b y Pa x Va x , t he n, dis car di n g 50 m L of t he 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 2 9  of 6 1  
b uffer s us p e nsi o n.  T his will hal ve t he v ol u me of b uffer a d mi nistere d t o t he y o u n gest c hi l dre n. 
T he vacci ne sac het is t he n e m ptie d i nt o t h e o pa q ue c o ntai ner c o ntai ni n g 5 0 m L of t he b uffer 
s ol uti o n, a n d t he mi xt ure is stirre d f or at least 3 0 s ec o n ds.  V A X C H O R A m ust be c o ns u me d wit hi n 
1 5 mi n utes of rec o nstit uti o n. Eac h s u bject will i m bi be t he 5 0  m L of li q ui d t o w hic h s he/ he is 
all ocate d.  
4. 2  
Pl ace b o  
Place b o will be 1 0 0  m L  (f or C o h ort 1 a n d 2) a n d 5 0 m L (f or C o h ort 3) n or mal ( 0. 9 %) sali ne. T he 
place b o will n ot be matc he d t o t he vacci ne vis uall y or b y taste . Place b o ( p h ysi ol o gical sali ne) will 
be dis pe nse d i n a n o pa q u e c u p. S u bjects will be as ke d n ot t o disc uss t he taste of t h e pr o d uct wit h 
ot her st u d y s u bjects.  
4. 3  
St u d y V acci ne Acc o u nt a bilit y  
Pa x Va x will s u p pl y st u d y vacci ne (V A X C H O R A  or place b o) , p urifie d b ottle d water  a n d o pa q u e 
c u ps t o all st u d y sites.  
It is t he res p o nsi bilit y of t he I n v esti gat or t o s u per vise acc urate m o nit ori n g of t he recei pt, st ora ge, 
dis pe nsi n g, a n d acc o u nti n g of all st u d y material acc or di n g t o acce pt e d me di cal a n d p har mace utical 
practice. Sites m ust retai n acc urate, ori gi nal site rec or ds of st u d y material i n ve nt or y as well as 
c o pies of all i n v oices of st u d y material s hi p me nts a n d rec or ds of st u d y mat erial dis p ositi o n.  
Dr u g acc o u nt a bilit y f or ms will be use d f or trac ki n g st u d y material (e .g ., date material was 
recei v e d, dis pe nse d t o i n di vi d ual s u bjects, a m o u nt use d a n d u n use d o n site, etc.). 
Eac h site m ust kee p all u n use d st u d y materi al u ntil t he St u d y M o nit or eit her arra n g es ret ur n t o 
Pa x Va x or t heir d esi g nee or gi ves i nstr ucti o n f or t heir dis p osal.  
4. 4  
St u d y V acci ne Dis pe nsi n g  
T he U n bli n de d P har macist ( or desi g nate d st u d y staff) will dis pe nse st u d y vacci ne t o t he u nbli n de d 
D ose A d mi nistrat or acc or di n g t o eac h s u bject’s tr eat me nt assi g n me nt . S u bjects s h o ul d be d ose d 
b y t he u nbli n de d D os e A d mi nistrat or at Da y 1.  I n s o me cases, t h e f u ncti o ns of t he U n bli n de d 
P har macist a n d D ose A d mi nistrat or ma y be perf or me d b y t he sa me pers o n. Eac h site m ust kee p a 
Site -S pecific Bli n di n g Pla n a n d res p o nsi ble i n di vi d uals m ust si g n o n t he pla n.  
U n bli n de d P har macist ( or desi g nate d staff) a n d u n bli n de d D ose A d mi nistrat or will n ot be i n v ol ve d 
i n p ost-vacci nati o n assess me nts a n d e val uati o n of V A X C H O R A acce pta bilit y a n d palata bilit y.  
 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 3 0  of 6 1  
5  
S T U D Y  P R O C E D U R E S  
5. 1  
I nf or me d C o nse nt 
Pri or t o a n y st u d y -relate d acti vities, t he s u bject’s pare nt or le gal g uar dia n m ust si g n a n d date a n 
I nstit uti o nal Re vie w B oar d (I R B)-a p pr ov e d I nf or me d C o nse nt F or m (I C F). S u bjects wit hi n t he 
ol der C o h ort 1 ( ≥1 2 t o < 1 8 y) will pr o vi de writte n asse nt. S u bjects i n C o h ort 2 ma y  pr o vi de writte n 
asse nt per eac h I R B’s rec o m me n dati o n. Refer t o Secti o n 1 0. 3  f or I CF g ui deli nes.  
5. 2  
Scree ni n g Pr oce d ure  
All s u bjects will u n der g o scree ni n g pr oce d ures aft er at least o ne pare nt or le gal g uar dia n has gi ve n 
t heir writte n, i nf or me d c o nse nt f or t heir c hil d t o partici pate i n t he st u d y. S u bjects  i n t he ol dest a ge 
c o h ort ( ≥1 2 t o < 1 8 y) will a d diti o nall y pr o vi de t heir writte n asse nt t o partici pate i n t he st u d y.   
T he st u d y ce nters will assi g n a u ni q ue, se q ue ntial s u bject n u m ber t o eac h s u bject w h o pr o vi des 
writte n c o nse nt. U p o n c o m pleti o n of all Scree ni n g Visit pr oce d ures  (Secti o n 6. 1. 1 ) a n d 
deter mi nati o n of eli gi bilit y, s u bjects will be sc he d ule d t o ret ur n f or t he Da y 1  Visit. Scree n i n g 
Visit pr oce d ures m ust be c o m plete d n o m ore t h a n 3 0  da ys bef ore t he Da y 1 Visit, b ut ma y be 
perf or me d t h e sa me d a y as t he Da y 1 visit.  
A scree ni n g l o g will be mai ntai ne d at t he cli nical researc h site t o rec or d t he reas o n(s) f or e xcl usi o n 
fr o m st u d y f or all s u bjects w h o si g n t he i nf or me d c o nse nt a n d u n der g o scree ni n g. 
5. 3  
Re -Scree ni n g Pr oce d ure  
T here ma y b e sit uati o ns i n w hic h a s u bject is n ot a ble t o be ra n d o mize d wit hi n 3 0  da ys of t heir 
i nitiall y sc he d ule d Da y 1 Visit. I n t hese i nsta nces, t he s u bject ma y n ee d t o be re -scree ne d. T his 
will i n v ol ve u n der g oi n g all  scree ni n g pr oce d ures a gai n. S u bjects ma y b e re-s cree ne d o ne ti me 
o nl y .  
5. 4  
R a n d o miz ati o n Pr oce d ure  
O n Da y 1 pre -v acci nati o n, me dical hist or y a n d c o nc o mita nt me dicati o ns will be u p date d i n t he 
s u bject file a n d n e gati ve uri ne pre g na nc y t est c o nfir me d, if a p pli ca ble, a n d bl o o d c ollecte d f or 
i m m u ne res p o nse assess me nts. T he I n v esti gat or will c o nfir m a n d d oc u me nt t he eli gi bilit y of eac h 
s u bject i m me diatel y pri or t o ra n d o mizati o n. S u bjects will be c o nsi dere d e nr olle d o n ce a 
ra n d o mizati o n n u m ber has bee n assi g ne d.  Dele gate d site staff u sers will e nr oll eac h s u bject b y 
assi g ni n g a n d e nteri n g a S u bject I D # i n t h e  Electr o nic Dat a C ollecti o n ( E D C) s yste m. T he E D C 
user will access t he i nte grate d ra n d o mizati o n f u ncti o n wit hi n t he E D C s yste m t o ra n d o mize t he 
s u bject t o o ne of t he treat me nt ar ms.  S u bjects will be ra n d o mize d at u p t o 3 0 cli nical researc h sites. 
T he assi g ne d tr eat me nt will a p pear o nl y o n t he  ra n d o mizati o n sc he d ule t hat will be deli vere d t o 
u n bli n de d st u d y pers o n nel  bef ore t he y e nr oll s u bject(s) at t heir site . Bli n de d st u d y pers o n nel will 
pri nt t he ra n d o mizati o n n u m ber f or eac h s u bject fr o m t he E D C ra n d o mizati o n f or m a n d ta ke it t o 
t he u n bli n de d  pers o n nel, w h o will matc h t he ra n d o mizati o n n u m ber t o t he ra n d o mizati o n sc he d ule 
a n d dis pe nse t he ass o ciat e d treat me n t. 
T he st u d y will be c o n d ucte d as a d o u ble -bli n d st u d y  t hr o u g h Da y 1 8 1 , w here neit her t he s p o ns or, 
t he statistical tea m, st u d y v ol u nteer s u bjects, n or cli nical site pers o n nel (e x ce pt f or t he u n bli n de d 
staff), will k n o w s u bjects’ treat me nt assi g n me nt. O nce eac h s u bject h as reac he d t heir Da y 1 8 1 visit 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 3 1  of 6 1  
t he y will be i n di vi d uall y u n bli n de d. O nce all safet y a n d i m m u n o ge nicit y data ha ve bee n recei ve d 
fr o m t he Da y 1 8 1  visit  a n d t he data clea ne d, a n d si g ne d b y t he PI, pre ve nti n g f urt her c ha n g es , t he 
bi ostatistics gr o u p 
will carr y o ut t he pri mar y a nal ysis. S u bjects, cli nical  site pers o n nel, 
In v esti gat ors  a n d t he s p o ns or will re mai n bli n de d u ntil eac h s u bject has c o m plete d t heir  Da y 1 8 1  
visit . Eac h s u bject is u n bli n de d i n di vi d uall y at Da y 1 8 1 a n d at t h at ti me t heir acti ve/ place b o stat us 
will be rec or de d i n t he E D C.  Refer t o t he c urre nt versi o n of P X V X -V C -2 0 0 -0 0 6  U n bli n di n g Pla n.  
5. 5  
Bli n di n g S afe g u ar ds  
A n u m ber of meas ures, d escri be d  bel o w, will be u n derta ke n i n or d er t o m ai ntai n t he bli n d o n t his 
trial. Meas ures i ncl u d e: 
a)  A d mi nistrati o n of st u d y vacci ne i n a n o pa q ue c o ntai ner. 
b)  T he ra n d o mizati o n sc h e d ule will be l oa de d i n t he E D C s yste m at t he b e gi n ni n g of t he 
st u d y. Treat me nt i nf or m ati o n will be a vaila ble o nl y t o t he u n bli n de d site pers o n nel o n a 
per -s u bject b asis u p o n ra n do mizati o n of eac h s u bj ect  or dis pe nsati o n of tr eat me nt . 
c)  At eac h  site t here will be u n bli n de d pers o n nel w h o pre pare a n d dis pe nse V A X C H O R A a n d 
Place b o, a n d a d mi nister t he vacci nati o n . All u n bli n de d pers o n nel will a gree n ot t o pr o vi de 
a n y i nf or mati o n or d oc u m e ntati o n t o t he s u bjects or bli n de d staff me m bers t hat ma y re v eal 
t he treat me nt assi g n me nt. T he u n bli n de d pers o n nel will n ot be i n v ol ve d i n a n y o bser vati o n, 
m o nit ori n g, or re p orti n g re q uire d b y t he st u d y pr ot oc ol, ot her t ha n 
st u d y vacci ne 
a d mi nistrati o n, st u d y vacci ne  acc o u nta bilit y  a n d dis pe nsi n g rec or ds.  
d)  S u bjects will be as ke d n ot t o disc uss t he taste of t he pr o d uct wit h ot her st u d y s u bjects as 
a p pr o priate f or a g e a n d c o g niti ve le vel.  
e)  S h o ul d a n y s u bject or bli n de d staff me m ber bec o me i na d vert e ntl y u n bli n de d f or a n y 
reas o n, t he e v e nt will be pr o m ptl y discl ose d t o t he I n v esti gat or s o t hat c orrecti ve acti o n 
ca n b e i nitiate d i n c o ns ultati o n wit h Pa x Va x. T h e u n bli n di n g se q ue n ce of e ve nts will be 
d oc u me nte d a n d retai n e d as s o urce d oc u me nts. A pr ot oc ol de viati o n will be e ntere d i n t he 
e C R F. 
5. 6  
Me dic al Hist or y  
Me dical hist or y i nf or mati o n c ollecte d fr o m s u bjects ( or p are nts or l e gal g u ar dia n) s h o ul d i ncl u de 
( b ut n ot be li mite d t o) d e m o gra p hic i nf or m ati o n, c urre nt a n d past me di cal c o n diti o ns, a n d c urre nt 
me dicati o ns t a ke n wit hi n 3 0 da ys of vacci nati o n. T he me dical hist or y m ust be d oc u me nte d i n t he 
s u bject’s st u d y c hart (t he o n-site s o urce d oc u me nt) pri or t o st u d y vacci ne a d mi nistrati o n a n d als o 
rec or de d o n t he Me dic al Hist or y electr o nic case re p ort f or m ( eC R F)  a n d t he de m o gra p hics eC R F .  
Me dicati o ns i ncl u di n g n o n-st u d y vacci nes m ust be d oc u me nte d i n t he s o urce d oc u me nts as well 
as o n t he p ri or a n d co nc o mita nt m e dicati o ns eC R F  a n d Vacci ne Hist or y e C R F .  
5. 7  
P h ysic al E x a mi n ati o n  
A c o m plete p h ysical e x a mi nati o n will be perf or m e d o n s u bjects d uri n g scree ni n g.  
T he e xa mi nati o n will  i ncl u de: 
Hei g ht  
B o d y Wei g ht  
Hea d -Nec k  

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 3 2  of 6 1  
E yes -E ars -N ose -T hr oat  
M usc ul os keletal  
L y m p h N o des  
L u n gs -C hest  
Heart  
A b d o me n  
Ot her b o d y s yste m if a p plica ble  
All p h ysical e xa m fi n di n gs m ust be d oc u me nte d i n t he s u bject’s st u d y c hart a n d als o rec or de d o n 
t he a p pr o priat e e C R F. 
5. 8  
Vit al Si g ns  
Vital Si g ns c ollecte d fr o m s u bjects d uri n g scree ni n g a n d/or at Da y 1 a n d Da y 1 8 1  (f or Place b o 
cr oss o ver s u bj ects) will i ncl u de bl o o d press ure, p ulse rate, res pirati o n  a n d te m perat ure all of w hi c h 
s h o ul d be rec or de d w he n t he s u bject is cal m a n d rea d y f or vital si g n assess me nt i n t he o pi ni o n of 
t he In v esti gat or . T e m perat ure  will be meas ure d orall y f or C o h ort 1 ( 1 2 t o < 1 8 years) a n d C o h ort 
2 ( 6 t o < 1 2 years) a n d oral is preferre d f or C o h ort 3 ( 2 t o < 6 y ears). F or C o h ort 3 s u bjects < 4, t he 
a xillar y te m perat ure ma y be meas ur e d if oral is n ot feasi ble. 
5. 9  
Pre g n a nc y Testi n g a n d C o ntr ace pti o n  
Fe male s u bjects w h o are of c hil d beari n g p ote ntial ( C o h ort 1 a n d C o h ort 2: a fe m ale s u bject is 
c o nsi dere d of c hil d beari n g p ote ntial f oll o wi n g me narc h e a n d u ntil bec o mi n g p ost -me n o pa usal 
u nless per ma ne ntl y steril e)  will u n der g o a  uri ne pre g na nc y test at scre e ni n g a n d pri or t o eac h st u d y 
vacci ne a d mi nistrati o n. T his will be d o ne usi n g a uri ne di pstic k. T he s u bject m ust n ot recei ve st u d y 
vacci ne if s he h as a p ositi ve pre g na n c y test at s cree ni n g or Da y  1 , or D a y 1 8 1 f or t he P lace b o 
cr oss o ver gr o u p . A n y pre g na ncies t hat occ ur i n fe males w h o ha ve recei ve d a st u d y vacci nati o n 
m ust be re p orte d pr o m ptl y t o Pa x Va x  as descri be d i n Secti o n 7. 7. 1 . 
Fe male s u bjects of c hil d beari n g p ote ntial m ust als o use a n acce pta ble met h o d of c o ntrace pti o n 
fr o m pri or t o Da y 1 t hr o u g h Da y 2 9  a n d fr o m Da y 1 8 1 t hr o u g h Da y 2 0 9  ( Place b o cr oss o v er 
s u bjects). Acce pta ble met h o ds i ncl u de hi g hl y effecti ve f or ms of c o ntrace pti o n s uc h as c o m bi ne d 
estr o ge n a n d pr o gest o ge n c o ntai ni n g or pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n ass ociate d wit h  
i n hi biti o n of o v ulati o n, I U D, i ntra ut eri ne h or m o ne-rel easi n g s yste m, bil ateral t u bal occl usi o n, 
a bsti ne nce or vasect o mi ze d part ner. T he I n v esti gat or m ust c o nfir m t hat c o ntrace pti o n met h o ds 
i nitiati o n pri or t o Da y 1 (e. g. h or m o nal c o ntr ace pti o n) are c o nsi dere d f ull y effecti ve pri or t o 
vacci nati o n.  
5. 1 0  V acci n ati o n  
O nce Da y 1 pre -v acci n ati o n pr oce d ures a n d ra n d o mizati o n are perf or me d , t he st u d y vacci ne 
( V A X C H O R A or place b o) will be gi ve n b y oral a d mi nistrati o n; s u bjects will recei ve n ot hi n g b y 
m o ut h (eat or dri n k) f or 6 0 mi n utes pri or t o a n d after t he  st u d y vacci ne a d mi nistrati o n  .  
S u bjects will be as ke d t o s wall o w t he st u d y vacci ne i n is olati o n of ot her s u bjects a n d i n t he 
prese nce of t he desi g n ate d u n bli n de d st u d y staff m e m ber. T h e s u bject will t he n re m ai n i n t he cli nic 
f or at least a 3 0-mi n ute o bser vati o n peri o d  w hic h t he bli n de d st u d y staff will m o nit or t he s u bject 
f or a n y si g ns of a n ac ute a d verse res p o nse t o t he v acci ne. 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 3 3  of 6 1  
5. 1 1  Acce pt a bilit y a n d P al at a bilit y A ssess me nts 
St u d y staff will ass ess t h e acce pt a bilit y of  t he st u d y vacci ne b ase d o n t he s u bject’s a bilit y t o ta ke 
t he st u d y vacci ne acc or di n g t o t he p har mac y ma n ual .  Cli nicall y si g nifica nt fi n di n gs i m me diatel y 
after c o ns u mi n g t he st u d y vacci ne will be re p orte d as ad verse e ve nts.  After c o m pleti o n of t he 3 0 -
mi n ute o bser vati o n peri o d, palata bilit y will be assesse d b y t he s u bject or care gi ver a n d re vie we d 
b y bli n de d st u d y staff usi n g a 5 -p oi nt He d o ni c scal e.  F urt her d etails will be pr o vi de d i n t he P X V X -
V C -2 0 0 -0 0 6 Ma n ual of Pr oce d ures . 
5. 1 2  I m m u ne Res p o nse Assessme nts  
Bl o o d sa m ples will be c ollecte d fr o m all s u bjects a n d ser u m will be teste d f or vi bri oci dal 
a nti b o dies. Ta ble 4  o utli nes t he ti me p oi nts f or vi bri oci dal assess me nts b y s u bject gr o u p.  
T a ble 4 : Bl o o d S a m ple C ollecti o n Ti m e P oi nts  
S u bject Gr o u p  
Ser u m  Vi bri oci d al 
A nti b o dies ( S V A) 
Assess me nt wit h Cl assic al 
I n a b a 
( St u d y D a ys) 
Bl o o d C ollecti o n f or 
Me m or y B Cell T est 
( St u d y D a ys) 
C o h ort 1  
1, 1 1, 2 9( ± 2), 9 1( ± 7), 1 8 1( ± 7)  1, 9 1( ± 7), 1 8 1( ± 7)  
C o h ort 2, 3  
1, 1 1, 2 9( ± 2)  
N A ( N ot A p plica ble)  
S u b -st u d y: L o n g -Ter m F oll o w -u p visit f or 
Acti ve Treat me nt gr o u p  i n C o h ort 1 
3 6 5( ± 1 4), 5 4 7( ± 1 4), 7 3 0( ± 1 4)  3 6 5( ± 1 4),  
5 4 7( ± 1 4), 
7 3 0( ± 1 4)  
Details  re gar di n g sa m ple c ollecti o n, pr ocessi n g a n d s hi p pi n g ca n be f o u n d i n t he P X V X -V C -2 0 0 -
0 0 6 La b orat or y M a n ual.  
5. 1 3  S olicite d A d verse E ve nts  
S olicite d a d verse e ve nts f or t his st u d y are: a b d o mi nal pai n, na us ea, v o miti n g, diarr hea, h ea dac he, 
lac k of a p petite, tire dness, a n d fe ver. Fr o m Da y 1 t hr o u g h Da y 8  (f or all s u bjects) a n d fr o m Da y 
1 8 1 t hr o u g h D a y 1 8 8 ( f or Place b o c r oss o ver s u bjects), t hese a d v erse e v e nts will be s olicite d fr o m 
s u bjects dail y i n t he e ve ni n g.  Bef ore disc har ge fr o m t he cli nic o n Da y 1 , all su bje cts will be trai ne d 
t o c o m plete a me m or y ai d  t o o bser ve, meas ure, a n d rec or d s olicite d A Es fr o m Da y  1  t hr o u g h Da y 
8 .  St u d y staff will re vie w t he si g ns a n d s y m pt o ms rec or de d o n t he me m or y ai d wit h t he s u bject t o 
c o nfir m se v erit y a n d relati o ns hi p t o st u d y vacci n e, a n d acti o n ta ke n f or t h e A E. T h e  me m or y ai d 
will be c ollecte d as a s o urce d oc u me nt. S olicite d a d verse e ve nts fr o m Da y 1 t hr o u g h Da y 8  will 
be rec or de d o n t he s olicite d a d vers e e v e nt e C R F.  S y m pt o ms c o nti n ui n g be y o n d Da y 8  wil l be 
rec or de d o n t he a d verse e ve nt e C R F. Acti o ns ta ke n f or s olicite d A Es  after Da y 8  s h o ul d be n ote d 
i n t he e C R F. Me m or y ai d re-distri b uti o n a n d retr ai ni n g t o c ollect s olicite d a d verse e v e nts fr o m 
Da y 1 8 1 t hr o u g h D a y 1 8 8  ( 7 d a ys after v acci nati o n) will be d o n e at Da y 1 8 1  ( vacci nati o n) f or 
Place b o cr oss o ver s u bjects. It will be re vi e we d b y t he st u d y staff at t he Da y 1 9 1 ( 1 0 da ys after 
vacci nati o n) visit.  

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 3 4  of 6 1  
5. 1 4  A d verse E ve nts  
All u ns olicite d a d verse e ve nts will be c ollecte d fr o m vacci nati o n Da y 1 t hr o u g h Da y 2 9  f or all 
s u bjects a n d fr o m D a y 1 8 1 t hr o u g h Da y 2 0 9 f or Place b o c r oss o ver s u bjects. Seri o us a d verse e v e nts 
will be c ollecte d  f or t he d urati o n of st u d y partici pati o n (i.e. starti n g at I nf or me d C o nse nt t hr o u g h 
Da y 1 8 1 f or all s u bjects, a d diti o nall y t hr o u g h Da y 3 6 5  f or Place b o cr oss o ver s u bjects, a n d 
a d diti o nall y t hr o u g h Da y 7 3 0  f or C o h ort 1 s u b-st u d y s u bjects).  I n C o h ort 2 a n d 3, e v e nts occ urri n g 
after D a y 2 9 ma y be ass esse d i nitiall y b y tele p h o ne c o nt act si nce t hese c o h orts d o n ot ha ve i n 
cli nic visits after Da y 2 9 . T he  details of eac h e ve nt will be rec or de d o n t he a p pr o priate C R F a n d 
i n t he s o urce d oc u me nt. T he re p orte d e ve nts ma y n ot re prese nt a v er bati m acc o u nti n g b y t he 
s u bject b ut s h o ul d reflect the cli nical j u d g me nt of t he st u d y staff.  Refer t o Secti o n 7  f or a d diti o nal 
details a b o ut e val uati n g a n d re p orti n g A Es.  
5. 1 5  Pri or a n d C o nc o mit a nt Me dic ati o ns  
Pri or a n d co nc o mita nt m e dicati o ns  at t he scree ni n g visit a n d eac h s u bse q ue ntl y sc he d ule d visit, 
t he details of pri or a n d c o nc o mita nt me dicati o n  usa ge will be c ollecte d a n d rec or de d o n t he 
a p pr o priate eC R F.  
Pri or a n d co nc o mita nt m e dicati o ns (i ncl u di n g n o n -st u d y v acci nes) s h o ul d be c ollecte d fr o m 3 0 
da ys pri or t o Da y 1 t hr o u g h Da y 1 8 1 f or all s u bjects, a n d t hr o u g h Da y 3 6 5  (6 m o nt hs after acti ve 
vacci nati o n) f or Place b o cr oss o ver s u bjects, a n d a d diti o nall y t hr o u g h Da y 7 3 0 f or C o h ort 1 s u b -
st u d y s u bjects. 
5. 1 6  P r o hi bite d Me dic ati o ns  
S u bject m ust n ot ha ve recei ve d or be pla n ni n g t o recei ve a n y ot her lice nse d vacci nes or a nti bi otics 
or c hl or o q ui ne fr o m 1 4 da ys pri or t o Da y 1 ra n d o mizati o n  t hr o u g h 1 1 da ys after  st u d y vacci ne 
a d mi nistrati o n . F or Place b o cr oss o ver s u bjects, t he s u bjects m ust n ot ha ve recei ve d  a n y ot h er 
lice nse d vacci nes or a nti bi otics or c hl or o q ui ne 1 4 da ys pri or t o Da y 1 8 1 , a n d t he s u bject m ust n ot 
be pla n ni n g t o recei ve a n y ot her lice nse d vacci nes or a nti bi otics or c hl or o q ui ne t hr o u g h 1 1 da ys 
after acti ve vacci nati o n. S u bjects m ust n ot ha ve recei v e d or be pla n ni n g t o recei ve a n y ot her 
i n vesti gati o nal a ge nts t hr o u g h o ut t he mai n st u d y u p t o Da y 1 8 1 a n d place b o cr oss o ver u p t o Da y 
3 6 5  (6 m o nt hs after acti ve vacci nati o n).  
5. 1 7  E mer ge nc y U n bli n di n g  
T he I n v es ti gat or ma y o btai n a treat me nt assi g n me nt bef ore Da y 1 8 1 f or a st u d y s u bject o nl y i n t he 
case of me di cal e mer ge n c y w here  k n o wle d ge of t he treat me nt is necessar y f or t he ma na g e me nt of 
a n a d verse e ve nt. T h e I n vesti gat or will n otif y t he S p o ns or ( Secti o n 7. 7. 4 ) i m me diatel y aft er 
u n bli n di n g, d oc u me nt t he reas o n a n d cir c u msta nces f or t he u n bli n di n g e ve nt, a n d distri b ute 
u n bli n di n g i nf or mati o n o nl y as nee d e d f or me dical ma na ge me nt. 
5. 1 8  Pr ot oc ol D e vi ati o ns  
T he I n v esti gat or is res p o nsi ble f or c o n d ucti n g t he st u d y i n acc or da n ce wit h t he pr ot oc ol. A n y 
de viati o n fr o m t he pr ot oc ol m ust be d oc u me nte d i n t he st u d y file. I n a d diti o n, de viati o ns m ust be 
re p orte d t o t h e I R B as a p plica ble. S u bject-s pecific de viati o ns m ust be rec or de d i n t he s u bject’s 
s o urce d oc u me nts a n d i n t he s u bject’s pr ot oc ol de viati o n e C R F.  T he S p o ns or will re vie w all 
pr ot oc ol de viati o ns o n a n o n g oi n g basis a n d will be res p o nsi ble f or cate g orizi n g pr ot oc ol 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 3 5  of 6 1  
de viati o ns as I m p ort a nt Pr ot oc ol De viati o ns (I P Ds).  I P Ds ma y re q uire a d diti o nal d oc u me ntati o n 
as re q ueste d b y t he S p o ns or.  
5. 1 9  C o m pleti o n of St u d y P artici p ati o n f or I n di vi d u al S u bjects 
A n i n di vi d ual s u bject  i n V A X C H O R A treat me nt gr o u ps of C o h ort 1, 2, a n d 3 is c o nsi dere d t o 
c o m plete st u d y partici pati o n after c o m pleti o n of t he Da y 1 8 1 (± 7)  visit a n d c o m pleti o n of a n y 
re q uire d safet y f oll o w-u p.  A n i n di vi d ual s u bject i n  t he Place b o cr oss o ver gr o u ps of C o h ort 1, 2, 
a n d 3 will be offere d  V A X C H O R A at t he Da y 1 8 1 visit  a n d is c o nsi dere d t o c o m plet e st u d y 
partici pati o n after c o m pl eti o n of t he Da y 3 6 5  (6 m o nt hs  after acti ve vacci nati o n) visit  if t he 
place b o cr oss o ver s u bject o pts t o recei ve V A X C H O R A . T he place b o  cr oss o ver s u bject w h o o pts 
n ot t o recei ve V A X C H O R A is c o nsi dere d t o c o m plet e at Da y 1 8 1.  A n i n di vi d ual i n t he l o n g-ter m 
foll o w -u p gr o u p of  t he C o h ort 1  s u b-st u d y is c o nsi dere d t o c o m plete st u d y partici pati o n after 
c o m pleti o n of t he Da y 7 3 0 (± 1 4)  visit a n d c o m pleti o n of a n y re q uir e d safet y f oll o w -u p.  
5. 2 0  E arl y Disc o nti n u ati o n  
A n  e nr olle d (ra n d o mize d) s u bject is c o nsi dere d t o u n der g o Earl y Disc o nti n u ati o n if t he y st o p st u d y 
partici pati o n bef ore t he st u d y c o m pleti o n visit da y of eac h gr o u p.   
A n e nr olle d s u bject ma y v ol u ntaril y wit h dra w c o nse nt  f or f urt her partici p at i o n at a n y ti me b ef ore 
t he d a y of st u d y c o m pleti o n . T he I n v esti gat or will re q uest ( b ut ca n n ot re q uire) s u c h s u bjects t o 
pr o vi de t he reas o n (s) f or wit h dra wal of c o nse nt a n d t o u n der g o a n Earl y Disc o nti n uati o n visit.  
I n a d diti o n, t he I n v esti gat or, at his or her dis creti o n, ma y wit h dra w a s u bject fr o m f urt her 
partici pat i o n i n t he st u d y. Criteria f or wit h dr a wal b y t he I n v esti gat or i ncl u de: 
•  N o nc o m plia nce wit h t he pr ot oc ol  
•  L os t t o f oll o w u p: l ost t o f oll o w u p re q uires d o c u me ntati o n of at l east 3 u ns uccessf ul 
atte m pts t o c o ntact s u bjects. L os t t o f oll o w u p will be deter mi ne d after s u bject’s pr oject e d 
last visit da y. 
•  A d verse e ve nt  
•  Ot her reas o n (s) w hic h, i n t he o pi ni o n of t he I n vesti gat or, i n dicat es t hat c o nti n ue d 
partici pati o n i n t he st u d y is n ot i n t he best i nteres t of t he s u bject 
5. 2 1  S u bject Re pl ace me nt  
S u bjects w h o u n der g o E arl y Disc o nti n uati o n  after ra n d o mizati o n a n d bef ore vacci nati o n ma y be 
re place d at t he S p o ns or’s  discreti o n. S u bjects w h o u n der g o Earl y Disc o nti n uati o n after v acci n ati o n 
will n ot be re place d. Neit her s u bject n u m bers n or r a n d o mizati o n n u m bers will be re use d.  
5. 2 2  St u d y C o m pleti o n  
T he st u d y is pla n ne d t o be c o m plete d  after all s u bjects ha ve c o m plete d t he pla n ne d visit s ( or Earl y 
Disc o nti n uati o n) , all necessar y s afet y f oll o w-u p has bee n c o m pl ete d, a n d all data q u eries are 
res ol ve d, t he e CR Fs are si g ne d b y t he I n vesti gat or, a n d t he data are l oc ke d. T he S p o ns or reser ves  
t he ri g ht t o ter mi nate t he st u d y pri or t o t he pla n ne d st u d y c o m pleti o n.  

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 3 6  of 6 1  
6  
S T U D Y P R O C E D U R E S  B Y VI SI T  
T he o verall s u m mar y of e val ua ti o ns b y visit is gi ve n i n t he Sc he d ule of E ve nts i n A p pe n di x  A .  
All visits are relati ve t o t he da y of vacci nati o n, Da y 1. Acce pta ble ti me wi n d o ws f or t he visit 
sc he d ule are i n dicate d. 
6. 1  
St u d y Visits  
6. 1. 1  Scree ni n g  Visit ( -3 0 D a ys t o D a y 1)  
T he f oll o wi n g will  ta ke place d uri n g t he visit: 
•  I nf or me d C o nse nt 
•  Me dical Hist or y  
•  Pri or a n d co nc o mita nt m e dicati o ns  
•  P h ysical E xa m  
•  Vital Si g ns  
•  Uri ne Pre g na n c y test (fe males of c hil d beari n g p ote ntial i n C o h ort s 1 a n d 2)  
•  I n cl usi o n/ E xcl usi o n Criteria 
 
6. 1. 2  D a y 1  
T he Da y 1 Visit m ust occ ur n o m ore t h a n 3 0  da ys after t he i nitial Scree ni n g Visit. All eli gi ble, 
c o nse nte d/asse nte d, a n d ra n d o mize d s u bjects are v acci nat e d at t his visit.  
T he f oll o wi n g will ta ke place d uri n g t he visit an d  pri or t o  st u d y vacci ne   a d mi nistrati o n : 
•  U p date d Me dic al Hist or y  
•  Directe d P h ysical E x a mi nati o n, if i n dicate d b y u p date d me dical hist or y  
•  Bl o o d C ollecti o n ( pre -d ose ) f or: 
o  Ser u m Vi bri oci dal A nti b o d y  ( S V A) 
o  Me m or y B cells f or C o h ort 1 o nl y  ( o pti o nal) 
•  Uri ne Pre g na n c y  test (fe males of c hil d beari n g p ote ntial) U p date d p ri or/co nc o mita nt 
m e dicati o ns   
•  Vital Si g ns  
•  C o nfir mati o n I n cl usi o n/ E xcl usi o n Criteria are still met  
•  Ra n d o mizati o n  
St u d y V acci ne  A d mi nistr ati o n:  

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 3 7  of 6 1  
S u bjects will ta ke n ot hi n g b y m o ut h (f o o d or  wat er) f or 6 0  mi n utes bef ore a n d after c o ns u m pti o n 
of  st u d y vacci ne. 
T he f oll o wi n g will ta ke place d uri n g t he visit a n d after  c o ns u m pti o n of st u d y vacci ne: 
•  I n-cli nic e v al uati o n of ac ute si de effects at least 3 0 mi n utes p ost -vacci nati o n  
•  Acce pt a bilit y/ Palata bilit y  e val uati o n  
•  A d verse eve nt ev al uati o n  
•  Me m or y Ai d - distri b uti o n a n d trai ni n g  
6. 1. 3  D a y  1 1  
T he f oll o wi n g will ta ke place d uri n g t he visit:  
•  Me m or y Ai d -c ollect a n d re vie w  
•  A d verse eve nt ev al uati o n i ncl u di n g S A E 
•  Bl o o d C ollecti o n f or:  
o  Ser u m Vi bri oci dal A nti b o d y ( S V A)  
•  U p date d co n c o mita nt m e dicati o ns  
6. 1. 4  D a y 2 9  ( ± 2) 
T he f oll o wi n g will ta ke place d uri n g t he visit: 
•   A d verse eve nt ev al uati o n i ncl u di n g S A E 
•  U p date d  co n c o mita nt m e dicati o ns   
•  Bl o o d collecti o n f or:  
o  Ser u m Vi bri oci dal A nti b o d y ( S V A)  
6. 1. 5  D a y 9 1  ( ± 7): 
a)  C o h ort 1  
T he  f oll o wi n g will ta ke place at t his visit: 
•  Seri o us ad verse e ve nt e v al uati o n  
•  U p date d co n c o mita nt m e dicati o ns   
•  Bl o o d C ollecti o n f or:  
o  Ser u m Vi bri oci dal A nti b o d y ( S V A)  
o  Me m or y B cells ( o pti o nal) 
b)  C o h ort 2 a n d 3  

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 3 8  of 6 1  
Tele p h o ne c o nt act is re q uire d t o assess t he f oll o wi n g: 
•  Seri o us ad verse e ve nt e v al uati o n  
•  U p date d  co n c o mita nt m e dicati o ns   
6. 1. 6  D a y 1 8 1  ( ± 7 d a ys): U n bli n de d  
a)  C o h ort 1  
T he  f oll o wi n g will ta ke place at t his visit  pri or t o u n bli n di n g : 
•  Seri o us ad verse e ve nt e v al uati o n  
•  U p date d  co n c o mita nt m e dicati o ns   
•  Bl o o d C ollecti o n f or:  
o  Ser u m Vi bri oci dal A nti b o d y ( S V A)  
o  Me m or y B cells ( o pti o nal) 
T he  f oll o wi n g will ta ke place at t his visit after u n bli n di n g : 
•  C o nse nt f or s u b -st u d y (f or t he Acti ve Treat me nt Gr o u p o nl y ) 
b)  C o h ort 2 a n d 3  
T he  f oll o wi n g will ta ke place at t his visit  pri or t o u n bli n di n g : 
•  Seri o us ad verse e ve nt e v al uati o n  
•  U p date d  c o n c o mita nt me dicati o ns   
c)  Pl ace b o  Cr oss o ve r  Gr o u ps o nl y  ( C o h ort 1, 2, 3): o pti o n al  
V A X C H O R A will be offere d t o t he s u bjects w h o were a d mi nistere d Place b o  o n Da y 1 after 
u n bli n di n g.  
T he f oll o wi n g  will  ta ke place d uri n g t his visit pri or t o Vacci nati o n : 
S u bjects will ta ke n ot hi n g b y m o ut h (f o o d or  water) f or 6 0  mi n utes bef ore a n d after vacci nati o n.  
•  Uri ne Pre g na n c y Test f or C o h ort 1 a n d 2  
•  Vital Si g ns  
T he f oll o wi n g will ta ke place d uri n g t he visit a n d after  vacci nati o n:  
•  I n-cli nic e v al uati o n of ac ute si de effects f or at least 3 0 mi n utes p ost -vacci nati o n  
•  Acce pt a bilit y/ Palata bilit y  e val uati o n  
•  A d v erse eve nt ev al uati o n  
•  Me m or y Ai d - distri b uti o n a n d trai ni n g  

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 3 9  of 6 1  
6. 1. 7  D a y 1 9 1  ( 1 0 d a ys after acti ve v acci n ati o n): f or  P l ace b o cr oss o ver gr o u p o nl y  
T he f oll o wi n g will ta ke place d uri n g t he visit:  
•  Me m or y Ai d  - c ollect i o n a n d re vie w  
•  A d verse eve nt ev al uati o n i ncl u di ng S A E  
•  U p date d co n c o mita nt m e dicati o ns  
6. 1. 8  D a y 2 0 9  (± 2)  ( 2 8 d a ys after a cti ve v a cci n ati o n ): f or Pl ace b o cr oss o ver g r o u p o nl y  
T he f oll o wi n g will ta ke place d uri n g t he visit:  
•  A d verse eve nt ev al uati o n i ncl u di n g S A E 
•  U p date d co n c o mita nt m e dicati o ns  
6. 1. 9  D a y 2 7 1  (± 7)  ( 9 0 d a ys after a cti ve v a cci n ati o n ): f or Pl ace b o cr oss o ver g r o u p o nl y 
Tele p h o ne c o nt act is re q uire d t o assess t he f oll o wi n g:  
•  Seri o us a d verse e ve nt e v al uati o n U p date d c o n c o mita nt me dicati o ns  
 
6. 1. 1 0  D a y 3 6 5  (± 7)  (6 m o nt hs  after a cti ve v a cci n ati o n ): f or Pl a ce b o cr osso v er gr o u p o nl y  
Tele p h o ne c o nt act is re q uire d t o assess t he f oll o wi n g:  
•  Seri o us a d verse e ve nt e v al uati o n  
•  U p date d c o n c o mita nt m e dicati o ns  
6. 1. 1 1  D a y 3 6 5  ( ± 1 4 d a ys)  f or l o n g ter m f oll o w-u p gr o u p (s u b -st u d y f or C o h ort 1 o nl y)  
T he  f oll o wi n g will ta ke place at t his visit: 
•  Seri o us ad verse e ve nt  e v al uati o n   
•  U p date d co n c o mita nt m e dicati o ns  
•  Bl o o d C ollecti o n f or:  
o  Ser u m Vi bri oci dal A nti b o d y ( S V A)  
o  Me m or y B cells ( o pti o nal) 
6. 1. 1 2  D a y 5 4 7  ( ± 1 4 d a ys)  f or l o n g ter m f oll o w-u p gr o u p (s u b -st u d y f or C o h ort 1 o nl y)  
T he  f oll o wi n g will ta ke place at t his visit : 
•  Seri o us A d verse E v e nt  e val uati o n  
•  U p date d co n c o mita nt m e dicati o ns  
•  Bl o o d C ollecti o n f or:  

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 4 0  of 6 1  
o  Ser u m Vi bri oci dal A nti b o d y ( S V A)  
o  Me m or y B cells ( o pti o nal) 
6. 1. 1 3  D a y 7 3 0  ( ± 1 4 d a ys)  f or l o n g ter m f oll o w-u p gr o u p (s u b-st u d y f or C o h ort 1 o nl y)  
T he  f oll o wi n g will ta ke place at t his visit : 
•  Seri o us ad verse eve nt  e v al uati o n  
•  U p date d co n c o mita nt m e dicati o ns   
•  Bl o o d C ollecti o n f or:  
o  Ser u m Vi bri oci dal A nti b o d y ( S V A)  
o  Me m or y B cells ( o pti o nal) 
6. 2  
E arl y  Disc o nti n u ati o n  Visit  
All s u bject s w h o disc o nti n ue  st u d y partici pati o n bef ore t he pla n ne d st u d y c o m pleti o n Da y  1 8 1  
visit will u n der g o a n  Earl y Disc o nti n uati o n  visit.  
If t he visit occ urs bef ore Da y 1 1 , t he f oll o wi n g will be c o n d ucte d:  
•  Re vie w S olicite d A Es, u ns olicite d A Es, a n d Seri o us A d verse E v e nts ( S A Es)  
•  U p date  c o n c o mita nt me dicati o ns ass ociate d wit h ne w or o n g oi n g A Es a n d a n y S A Es  
•  Bl o o d C ollecti o n f or: Ser u m Vi bri oci dal A nti b o d y ( S V A)  
If t he visit occ urs after Da y 11  a n d bef ore Da y 2 9, t he f oll o wi n g will be c o n d ucte d:  
•  Re vie w u ns olicite d A Es, a n d Seri o us A d verse E ve nts ( S A Es)  
•  U p date  c o n c o mita nt me dicati o ns ass ociate d wit h ne w or o n g oi n g A Es a n d a n y S A Es  
•  Bl o o d C ollecti o n f or: Ser u m Vi bri oci dal A nti b o d y ( S V A)  
If t he visit occ urs after Da y 2 9, t he f oll o wi n g will be c o n d ucte d: 
•  Re vie w Seri o us A d vers e E ve nts ( S A Es)  
•  U p date  c o n c o mita nt me dicati o ns ass ociate d wit h a n y S A Es  
•  Bl o o d C ollecti o n f or:  
o  Ser u m Vi bri oci dal A nti b o d y ( S V A)  
o  Me m or y B cells ( o pti o nal) : f or C o h ort 1 o nl y 
6. 3  
U nsc he d ule d Visits  
A d diti o nal  st u d y pr oce d ure(s) ma y b e c o n d ucte d at a n u nsc h e d ule d vis it as nee de d.  E xa m ples 
i ncl u de re peat s peci me n c ollecti o n a n d a d diti o nal safet y f oll o w -u p f or a n ad verse ev e nt.   

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 4 1  of 6 1  
7  
S A F E T Y  
7. 1  
Defi niti o n s 
7. 1. 1  A d verse E ve nt  
A n A d verse E ve nt ( A E) is a n y u nt o war d me dical occ urre nce i n a st u d y partici pa nt, re gar dless of 
t he s us pecte d ca usal r elati o ns hi p wit h st u d y vacci ne.  
T he defi niti o n of a n A E i ncl u des : 
•  A ne w -o nset s y m pt o m or disease  
•  A n e xacer bati o n of a pre -e xisti n g s y m pt o m or disease ( w orse ni n g i n fre q ue n c y or i nte nsit y) 
•  A ne w -o nset la b orat or y a b n or malit y c o nsi dere d b y t he I n vesti gat or t o be cli nicall y 
si g nifica nt 
•  A ne w -o nset s y m pt o m or disease t hat occ urs as a res ult of a pr ot oc ol -s pecifie d pr oce d ure 
T he defi niti o n of a n A E d oes n ot  i ncl u de: 
•  A pre -e xisti n g s y m pt o m or disease t hat d oes n ot w orse n d uri n g t he st u d y (e ve n if first 
discl ose d b y t he s u bject after t he start of t h e st u d y)  
•  A  me dical or s ur gical i nter ve nti o n s uc h as s ur ger y, e n d os c o p y, t o ot h e xtracti o n, or 
tra nsf usi o n (alt h o u g h t h e c o n diti o n lea di n g t o t he pr oce d ure or a c o m plicati o n fr o m t he 
pr oce d ure ma y be a n A E)  
•  A n u nc o m plicate d pre g n a nc y  
•  A  d osi n g err or wit h o ut a n y res ulti n g si g ns or s y m pt o ms  
•  A n y ot her sit uati o n w h ere a n u nt o war d me dical occ urre n ce has n ot occ urre d (e. g. 
h os pitalizati o n  f or c os metic electi ve s ur ger y or s o cial a d missi o ns) 
T he I n vesti gat or will  atte m pt t o esta blis h a dia g n osis base d o n si g ns, s y m pt o ms, a n d ot her cli nical 
i nf or mati o n. W he ne v er p ossi ble, t he I n vesti gat or will re p ort an A E as a  di a g n osis rat her t ha n o ne 
or m ore si g ns or s y m pt o m s. If a cli nicall y si g nifi ca nt la b orat or y a b n or malit y  meets t he defi niti o n 
of a n A E, a dia g n osis or cli nical si g ns a n d s y m pt o ms rat her t ha n t he a b n or mal la b orat or y fi n di n g 
s h o ul d be re p ort e d if p ossi ble. If n o dia g n osis is k n o w n a n d cli nical si g ns a n d s y m pt o ms are n ot 
prese nt, b ut t he la b orat or y a b n or malit y is cli nicall y si g nifica nt b y itself, t he n it s h o ul d be re p orte d 
as t he A E. 
7. 1. 2  S olicite d A d verse E ve nt  
A s olic ite d a d verse e ve nt (s olicite d A E)  is a pr ot o c ol-s pecifie d A E a b o ut w hic h t he I n vesti gat or 
or desi g nee pr oacti vel y as ks t he s u bjects d uri n g a pr ot oc ol -s pecifi e d ti me peri o d.  S olicite d a d verse 
e ve nts f or t his st u d y are: a b d o mi nal pai n, na usea, v o miti n g, dia rr hea, hea d ac he, lac k of a p petite, 
fe ver, tire d ness.  

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 4 2  of 6 1  
7. 1. 3  U ns olicite d A d verse E ve nt  
A n u ns olicite d a d verse e ve nt ( u ns olicite d A E) is a n A E t hat is s p o nta ne o usl y re p orte d b y t he 
s u bject or disc o vere d b y t he I n v esti gat or.  
7. 1. 4  Seri o us A d verse E ve nt  
A n S A E is a n A E (eit her s olicite d or u ns olicite d) w hic h meets a n y of t h e f oll o wi n g criteria:  
•  Res ults i n deat h  
•  Is life-t hreate ni n g 
•  Re q uires h os pitalizati o n or pr ol o n gs a n e xisti n g h os pitalizati o n  
•  Res ults i n a persiste nt cli nicall y si g nifica nt disa bilit y or i nca pacit y 
•  Is a c o n ge nital a n o mal y or birt h defect  
•  Re q uires  me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he a b o ve o ut c o mes  
•  Im p ort a nt me dical e v e nt  
T he I n vesti gat or will e v al uate all A Es f or seri o us ness usi n g  t he a b o ve criteria. 
“Life -t hr eate ni n g”  mea ns t hat i n t he o pi ni o n of t he I n v esti gat or, t he s u bject was at i m me diate ris k 
of deat h fr o m t he e v e nt as it occ urre d. It d oes n ot mea n t hat t he e ve nt  mi g ht ha ve ca use d d eat h ha d 
it occ urre d i n a m ore se v ere f or m. 
H os pitalizati o n f or o bser vati o n or f or electi ve tre at me nt of a pre -e xisti n g c o n diti o n t hat di d n ot 
w orse n d uri n g t he st u d y is n ot c o nsi dere d a n S A E.  
Im p ort a nt me dical e v e nts ma y be c o nsi dere d seri o us at t he discreti o n of t he I n v esti gat or. 
T hese seri o us n ess criteri a als o a p pl y t o t he St u d y St o p pi n g R ules i n Secti o n 7. 1 0 . 
7. 2  
Se verit y Gr a di n g  
T he I n v esti gat or  will gra de all a d vers e e v e nts f or se verit y .  A d verse e v e nt s liste d i n t he T o xi cit y 
Gra di n g Scale i n  A p pe n di x B  will be gra de d acc or di n g t o t he criteria i n t he ta ble .  A d verse e v e nts 
n ot liste d i n t he T o xicit y Gra di n g Scale will be gra de d as f oll o ws:  
•  Mil d ( Gra de 1) –  N o i nterfere nce wit h acti vit y  
•  M o derate ( Gra d e 2) –  S o me i nterfere nce wit h acti vit y  
•  Se vere ( Gra d e 3) –  Si g nifica nt; pre v e nts dail y acti vit y  
•  P ote ntiall y Life -T hreat e ni n g ( Gra de 4) –  E R visit or h os pitalizati o n  
•  Fatal ( Gra d e 5)  
T hese se verit y gra des als o a p pl y t o t he St u d y St o p pi n g R ules i n Secti o n 7. 1 0 . 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 4 3  of 6 1  
7. 3  
C a u s alit y Assess m e nt  
T he I n v esti gat or will assess all  A Es , i ncl u di n g s olicite d A Es, f or ca usalit y (relati o ns hi p t o st u d y 
vacci ne), assi g ni n g o n e of t hese t hree cate g ories: N ot Relate d, P ossi bl y Relate d, a n d Pr o ba bl y 
Relate d.  
A n A E will be c o nsi dere d “ N ot Rela te d” t o st u d y vacci n e if a n y  of t he f oll o wi n g c o n diti o ns  are 
met:  
•  A n u nreas o n a ble te m p oral relati o ns hi p bet wee n a d mi nistrati o n of t he st u d y vacci ne a n d 
t he o nset of t h e A E (e. g., t he e v e nt occ urre d eit her bef ore, or t o o l o n g aft er a d mi nistrati o n 
of t he st ud y vacci n e  f or it t o be c o nsi dere d relate d); 
•  A ca usal rel ati o ns hi p bet wee n t he st u d y vacci n e a n d t he A E is bi ol o gicall y i m pla usi ble 
(e. g. i nj ur y as a p asse n ger i n a n aut o m o bile acci de nt);  
•  A clear alter nati ve ca us alit y  f or t he A E is pres e nt (e. g. t y pical a d v erse reacti o n t o a 
c o nc o mita nt me dicati o n ). 
A n A E will be c o nsi d ere d “ P ossi bl y R elate d” if t here is a reas o na ble p ossi bilit y t hat t he A E  ma y 
ha ve bee n ca us e d b y t he st u d y vacci ne. 
A n A E will be c o nsi dere d “ Pr o ba bl y R elate d” if t here is e vi de nce t hat t he A E  was ca use d  b y t he 
st u d y vacci ne. 
7. 4  
F oll o w -u p of A d verse E ve nts  
T he I n v esti gat or m ust f oll o w a ll A Es u ntil res ol uti o n, u ntil t he c o n diti o n sta bilizes or is  n o l o n ger 
cli nicall y si g nifica nt, or u ntil t h e s u bject is l ost  t o f oll o w-u p.  T h e re q uire me nt f or f oll o w -u p 
i ncl u des s olicite d a d vers e e ve nts t hat c o nti n ue past Da y 8.  
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t he c o n d uct of a n y s u p ple me ntal i n vesti gati o ns 
c o nsi dere d necessar y t o e val uate t he A E. T hes e ma y i ncl u de  a d diti o nal la b orat or y tests or 
i n vesti gati o ns, 
hist o pat h ol o gical e xa mi nati o ns, 
or c o ns ultati o n 
wit h 
ot her 
healt h care 
pr ofessi o nals.  
I n t he e ve nt of a n o n-fatal S A E, s u bjects will be i nstr ucte d t o c o ntact t h e I n v esti gat or ( or desi g ne e) 
i m me diatel y. All s u bjects e x perie nci n g a n S A E will be e val uate d  b y  t he I n vesti gat or or desi g nee 
as s o o n as is feasi ble f oll o wi n g t he re p ort of t he S A E  b y t he s u bject .  In t he e ve nt of a fatal S A E, 
t he I n v esti gat or m ust pr o vi de t he S p o ns or wit h a n y a vaila ble p ost -m orte m fi n di n gs, i ncl u di n g 
hist o pat h ol o g y.  
A d diti o nall y, t he S p o ns or  ma y re q u est t hat t he I n vesti gat or perf or m or arra n ge f or t he c o n d u ct of 
s u p ple me ntal i n vesti gati o ns f or o ne or m ore A Es .  
7. 5  
Re p orti n g of A d vers e E ve nts  
7. 5. 1  Re p orti n g Peri o ds  
T he re p orti n g peri o d f or S A Es be gi ns at t he ti me of i nf or me d c o nse nt a n d c o nti n ues f or t he 
d urati o n of st u d y partici pati o n  ( Secti o n 5. 1 4). T he re p orti n g peri o d f or s olicite d A Es be gi ns after 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 4 4  of 6 1  
st u d y vacci ne a d mi nistrati o n o n Da y 1 a n d c o nti n ues t hr o u g h Da y  8 . T h e re p orti n g peri o d f or 
s olicite d A Es f or t he Place b o cr oss o ver s u bjects be gi ns after V A X C H O R A a d mi nistrati o n o n 
Da y  1 8 1 a n d c o nti n ues t hr o u g h Da y 1 8 8. T he re p orti n g peri o d f or all ot her A Es be g i ns after st u d y 
vacci ne a d mi nistrati o n o n Da y 1 a n d c o nti n ues t hr o u g h Da y 2 9 .  T h e re p orti n g peri o d f or all ot her 
A Es f or t he Place b o cr oss o ver be gi ns after V A X C H O R A  a d mi nistrati o n o n Da y 1 8 1 a n d c o nti n ues 
t hr o u g h Da y 2 0 9. A Es t hat c orres p o n d t o s olicite d A E ter ms a n d occ ur after Da y 8  or Da y 1 8 8 (f or 
Place b o cr oss o v er s u bjects) will be re p orte d as u ns olicite d A Es.  
7. 5. 2  D oc u me nt ati o n  
T he I n ve sti gat or or desi g nee will d oc u me nt all A Es i n t he s u bject’s s o urce d oc u me nts a n d e nter 
all u ns olicite d  A Es  or s olicite d A Es c o nti n ui n g after Da y 8  i n t he a d verse e ve nt e C R F wit hi n 
7  da ys of a w are n ess.  
All  u ns olicite d  A E s s h o ul d i ncl u de: 
•  E ve nt ter m  
•  Start a n d st o p date    
•  Se verit y  
•  Seri o us ness ( Yes/ N o) a n d Seri o us ness criteria m et  if a p plica ble 
•  Relati o ns hi p t o st u d y vacci ne  
•  Acti o n ta ke n i n res p o nse t o t he  A E  
7. 6  
S A E  Re p orti n g  
T he I n vesti gat or  or desi g nee  m ust re p ort all S A Es t o t he S p o ns or Me dical M o nit or wit hi n 2 4 h o urs 
of t heir a ware ness  of t he e ve nt  b y fill i n g o ut t he pa per S A E F or m  a n d se n d t o  
. T he I n vesti gat or  or desi g nee m ust als o e nter S A Es i n t he 
a d verse e ve nt e C R F.  
T he S A E F or m s h o ul d b e c o m plete d as t h or o u g hl y as p ossi ble a n d si g ne d b y t he I n vesti gat or or  
desi g nee b ef ore re p orti n g t o t he S p o ns or Me dical M o nit or . T he S A E F or m m ust i ncl u de a n 
assess me nt of ca usalit y  a n d s h o ul d i ncl u de a preli mi nar y dia g n osis if p ossi ble . 
I n or der t o a v oi d dela ys i n i nitial re p orti n g, ad diti o nal i nf or mati o n  re gar di n g t he S A E ma y be 
pr o vi de d as a f oll o w -u p re port.  T he I n vesti gat or ma y als o m o dif y t he dia g n osis, seri o us ness, 
a n d/ or ca us alit y assess me nt base d o n t his i nf or mati o n.  
T he S p o ns or Me dical M o nit or will n otif y t he I n v esti gat or of S A Es t hat meet criteria f or  e x p e dite d 
re p orti n g t o re g ulat or y a ut h orities.  T he I n v esti gat or is res p o nsi ble f or n otif yi n g t he a p plica ble I R B 
of t hese e v e nts  a n d a d heri n g t o a n y ot her a p plica bl e l ocal re p orti n g re q uir e me nts . 
T he S p o ns or will re p ort a d verse e ve nts t o F D A i n acc or da nce wit h 2 1 C F R 3 1 2. 3 2.  S pecificall y, 
t he S p o ns or will re p ort u ne x pecte d fatal or life -t hreate ni n g s us pecte d a d v erse reacti o ns n o later 
t ha n 7 da ys after i nitial recei pt of t he i nf or m ati o n, a n d seri o us a n d u n e x pecte d s us pecte d a d verse 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 4 5  of 6 1  
reacti o ns ( S U S A Rs) n o later t ha n 1 5 cal e n dar d a ys after deter mi ni n g t hat t he i nf or mati o n q ualifies 
f or e x pe dite d re p orti n g.   
7. 7  
Ot her E ve nts  Re q uiri n g I m me di ate Re p orti n g  
7. 7. 1  Pre g n a nc y  
T he 
I n v esti gat or 
or 
desi g nee 
m ust 
s u b mit 
t he 
Pre g na nc y 
Re p ort 
F or m 
t o 
 wit hi n 2 4 h o urs of t heir a ware ness of t he pre g n a nc y . All 
pre g na nci es will b e f oll o we d t o o ut c o me . A d diti o nal i nf or mati o n  re gar di n g t he pre g na n c y ma y be 
pr o vi de d as a f oll o w -u p re p ort.  
A n u nc o m plicate d pre g n a nc y is n ot c o nsi dere d a n A E. C o m plicati o ns of pre g na nc y ma y q ualif y 
as A Es or S A Es a n d w o ul d t heref ore be d oc u m e nte d a n d re p orte d as s p ecifi e d a b o ve .   
7. 7. 2  D osi n g Err or s 
T he  I n vesti gat or or desi g nee m ust re p ort a n y err or i n t he d osi n g of st u d y vacci ne t o t he S p o ns or 
Me dical M o nit or i n a bli n de d ma n ner, a n d re p ort a n y u n bli n di n g i nf or mati o n t o t he u n bli n de d 
C R A wit hi n 2 4 h o urs of t heir a ware ness of t he err or . A d diti o nal i nf or m ati o n  re g ar di n g t he d osi n g 
err or ma y be pr o vi de d as a f oll o w -u p re p ort.  A d osi n g err or wit h o ut si g ns or s y m pt o ms is n ot 
c o nsi dere d a n A E , b ut is a pr ot oc ol de viati o n a n d ma y be d eter mi ne d t o b e a n I P D.  
7. 7. 3  E arl y Disc o nti n u ati o n  f or S afet y Re as o ns 
T he I n vesti gat or or d esi g nee m ust re p ort a n y earl y disc o nti n uati o n f or safet y reas o ns  t o t he 
S p o ns or Me dical M o nit or wit hi n 2 4 h o urs of disc o nti n uati o n  (Secti o n 7. 6 ). A d diti o nal i nf or mati o n 
re gar di n g o n g oi n g a d vers e e ve nts ma y be pr o vi de d as a f oll o w -u p re p ort.   
7. 7. 4  E mer ge nc y U n bli n di n g f or S afet y Re as o ns  
T he I n vesti gat or or desi g nee m ust re p ort e mer g e n c y u n bli n di n g  to t he S p o ns or ’s Me dical M o nit or 
i n a bli n de d ma n ner wit hi n 2 4 h o urs  of u n bli n di n g. T he I n vesti gat or or d esi g nee m ust fill o ut t he 
U n bli n di n g Re q uest F or m a n d se n d t o  
 a n d ca n 
disc uss a n y u n bli n di n g i nf or mati o n wit h t he u n bl i n de d C R A.  A d diti o nal i nf or mati o n  re gar di n g 
t he u n bli n di n g, e xcl u di n g t he act ual tr eat me nt assi g n me nt, ma y be pr o vi de d as a f oll o w -u p re p ort.  
7. 8  
Me dic al M o nit or  
T he S p o ns or Me dic al M o n it or (S M M) will pr o vi de s afet y o versi g ht f or t he st u d y. T he S M M or 
desi g nee will re vie w bli n de d  st u d y data a n d ass ess ca usalit y of S A Es o n a n o n g oi n g basis.  
Na me:  
 
 
Title:  
 
 
A d dress:  
 
 
 
 
 
Re d w o o d Cit y, 
 
Tele p h o ne :  
 
 
Fa x : 
 
 
E mail:  
 
 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 4 6  of 6 1  
7. 9  
S afet y M o nit ori n g C o m mittee  ( S M C) 
A Safet y M o nit ori n g C o m mittee ( S M C) will be a p p oi n te d t o c o n d u ct peri o dic re vi e w  of all 
a vaila ble i nteri m, bli n de d safet y dat a  fr o m si m ulta ne o us e nr oll me nt fr o m all a ge c o h orts e ver y 6 
m o nt hs w hile st u d y acti vities are o n g oi n g . T he S M C will be c o m p ose d of t w o i n de pe n d e nt  
p h ysicia ns  a n d o ne i n d e p e n de nt statisticia n. T h e S M C c harter will o utli ne t he s pecific d ata t o be 
re vie we d a n d t he c o m m u nicati o n pla n. 
7. 1 0  St u d y St o p pi n g R ules  
E nr oll me nt will be st o p pe d f or a n y of t he f oll o wi n g:  
1.  A n y deat h or S A E e x p eri e nce d b y a s u bject, r e gar dless of ca usalit y;  
2.  O ne or m ore s u bjects wit h a Gra de 3 (se vere) or greater A E assesse d as p ossi bl y or 
pr o ba bl y  relat e d t o t he st u d y vacci ne. 
T he i n vesti gat or or desi g nee m ust s us pe n d e nr oll me nt a n d n otif y t he 
Me dical 
M o nit or at 
 wit hi n 2 4 h o urs of bec o mi n g 
a ware of a n e ve nt t h at meets eit her of t he a b o ve r ules. N o s pecific n otificati o n f or m is re q uire d. 
E nr oll me nt ma y be res u me d f oll o wi n g re vie w of a vaila ble safet y data b y t he S p o ns or ’s Me dical 
M o nit or a n d Safet y M o nit ori n g C o m mittee  a n d after t he S p o ns or’s Me dical M o nit or has  n ot ifie d 
t he I n v esti gat or t hat e nr oll me nt ma y res u me.  
F or f urt her i nf or mati o n re gar di n g Safet y pr oce d ures, please refer t o t he P X V X -V C -2 0 0 -0 0 6  Safet y 
Ma na ge me nt Pla n ( S M P)  a n d P X V X -V C -2 0 0 -0 0 6 S M C C harter . 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 4 7  of 6 1  
8  
D A T A H A N D LI N G  
8. 1  
S o urce D oc u me nt ati o n  
T he I n vesti gat or 
m u st 
mai ntai n s o urce d oc u m e ntati o n of all st u d y c o n d uct a n d data a n d 
o bs er vati o ns rele v a nt t o t he st u d y.  T his  s o urce d oc u me ntati o n i ncl udes, b ut is n ot li mite d t o, I C Fs, 
ori gi nal me dical rec or ds, pr o gress  n otes fr o m t he I n v esti gat or a n d st u d y staff, la b orat or y re p orts, 
me m or y ai d s f or s olicite d a d verse e v e nts, a n d d oc u me ntati o n of st u d y vacci ne acc o u nt a bilit y. T he 
i n vesti gat or ma y kee p electr o nic s o ur ce d oc u m e ntati o n per S p o ns or’s re q u est. 
8. 2  
C ase Re p ort F or ms  
T his st u d y will e m pl o y e lectr o nic Cas e Re p ort F or ms  (e C R Fs) pr o vi de d b y t he S p o ns or. C ertai n  
cli nical i nf or mati o n re q ueste d i n t his p r ot oc ol will be rec or de d o n t hese eC R Fs . T he I n vesti gat or 
is res p o nsi ble f or t he a de q uac y a n d acc urac y of all data e ntere d o n t he e C R Fs.  T he I n v esti gat or is 
als o res p o nsi ble f or si g ni n g all e C R Fs, after w hic h t he y will be l oc ke d t o pre ve nt f urt her d ata e ntr y 
or m o dificati o n.  
F or f urt her i nf or mati o n o n e C R Fs, pleas e refer t o t he P X V X -V C -2 0 0 -0 0 6 C R F C o m pleti o n 
G ui deli nes. F or f urt her i nf or mati o n re g ar di n g d at a ha n dli n g, please refer t o t he P X V X -V C -2 0 0 -
0 0 6  Data Ma n a ge me nt Pla n ( D M P).  
8. 3  
Rete nti o n of  St u d y D oc u me nt ati o n  
T he I n vesti gat or m ust ma ke st u d y data accessi ble t o t he m o nit or, ot her a ut h orize d re prese nt ati ves 
of Pa x Va x (a n d/ or  its desi g nee), a n d re g ulat or y a ge ncies (e.g ., F D A) i ns p ect ors u p o n re q u est. A 
file f or eac h s u bject m ust be mai ntai ne d t hat i ncl u des t he si g ne d I C F a n d all s o urce d oc u m e ntati o n 
relate d t o t hat s u bject. T he I n v esti gat or m ust e ns ure t he relia bilit y a n d a vaila bilit y of s o urce 
d oc u me nts fr o m w hic h t he i nf or mati o n o n t he eC R F was deri ve d. I n v esti gat ors are re q uire d t o 
mai ntai n all st u d y d oc u me ntati o n, i ncl u di n g c o pies of eC R Fs, I C Fs, a n d a d e q uate rec or ds f or t he 
recei pt a n d dis p ositi o n of all st u d y me dicati o ns, f or a peri o d of 2 years f oll o wi n g t he F D A or ot her 
re g ulat or y a p pr o val of V A X C H O R A, or 2 y ears after cli nical de vel o p me nt of V A X C H O R A is 
disc o nti n ue d, u nless a l o n ger peri o d is re q uir e d b y a p plica ble la w or re g ul ati o n.  T he I n v esti gat or 
will destr o y st u d y  d oc u me ntati o n o nl y u p o n i nstr ucti o n b y t he S p o ns or a n d m ust n otif y t he 
S p o ns or u p o n c o m pleti o n of s uc h destr ucti o n .  S u bject i de ntit y i nf or mati o n will be mai ntai ne d f or 
1 5 years u nless a l o n g er peri o d is re q uire d b y a p plica ble la w or re g ulati o n.  
8. 4  
D at a M o nit ori n g  
T he S p o ns or or desi g ne e will m o nit or c o m plete d e C R Fs a g ai nst s o urce d o c u me ntati o n at re g ular 
i nter vals t hr o u g h o ut t he st u d y t o verif y a d here n ce t o t he pr ot oc ol, c o m plete ness, acc urac y, a n d 
c o nsiste nc y of t he data , a n d a d here n ce t o l ocal re g ulati o ns o n t he c o n d uct of cli nical researc h. T he 
I n v esti gat or m ust ma ke s o urce d oc u me ntati o n accessi ble t o t he S p o ns or or desi g nee as nee d e d t o 
verif y t he i nf or m ati o n i n t he eC R Fs.  T he I n v esti gat or a grees t o c o o perat e wit h t he S p o ns or or 
desi g nee  t o e ns ure t hat a n y pr o ble ms detecte d i n t he c o urse of data m o nit ori n g are res ol ve d.  
8. 5  
L a b or at or y D at a  
T his st u d y will e m pl o y electr o nic tra nsfers of e xter nal la b orat or y data g enerat e d fr o m cli nical 
s peci me ns c ollect e d b y t he I n vesti gat or . T h e I n vesti gat or is res p o nsi ble f or t he ade q uac y a n d 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 4 8  of 6 1  
acc urac y of data ass oci ate d wit h c ollecti o n of t hese s peci me ns.  T h e S p o ns or or desi g ne e is 
res p o nsi ble f or t he a de q u ac y a n d acc urac y of t he d ata ge nerate d b y e xter nal la b orat ories. 
8. 6  
A u dit C o m pli a nce  
T he I n vesti gat or m ust per mit t he S p o ns or a n d/or desi g nee, re g ul at or y a g e ncies , a n d/ or t he I R B 
direct access t o facilities a n d st u d y d oc u me ntati o n f or t he p ur p ose of a u diti n g st u d y c o n d uct.  
Direct access i ncl u des e x a mi ni n g, a nal yzi n g, verif yi n g, a n d re pr o d uci n g a n y rec or ds a n d re p orts 
t hat are nee de d f or t he e v al uati o n of t he st u d y. 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 4 9  of 6 1  
9  
S T A TI S TI C A L A N A L Y SI S   
9. 1  
S a m ple Size C alc ul ati o n  
Ass u mi n g t hat t he tr ue ser oc o n versi o n rate a m o n g 1 2 t o < 1 8 -year -ol ds is 9 2. 4 % or hi g her, t he 
sa m ple size of 1 4 3 e v al u a ble  vacci ne es f or t hat a ge c o h ort aff or ds 9 3 . 3 % p o wer t o d e m o nstrate 
t hat t he ser oc o n v ersi o n rate wit hi n t he gr o u p is n o n-i nferi or t o t he 9 4 % rate o bser ve d i n t he 2 6 8 7 
a d ult s u bjects assess e d i n t he Pa x Va x l ot -c o nsiste nc y trial, P X V X -V C -2 0 0 -0 0 4 . T he s a m ple siz e 
all o ws f or u p t o 5 % of s u bjects t o be n ot e val ua ble f or t he pri mar y i m m u n o ge nicit y a nal yses i n 
t he t w o ol der c o h orts (a ges 6 t o < 1 8). Base d o n t he i ne val ua ble rate o bser ve d t o  date , it is esti mate d 
t hat a p pr o xi matel y 3 0 % of s u bjects i n t he y o u n gest c o h ort (a ges 2 t o < 6) will be i ne val ua ble, 
m ostl y d ue t o lac k of c o ns u m pti o n of t he f ull d ose .  A s d efi ne d i n t h e al p ha-s pe n di n g strat e g y 
descri be d i n Secti o n 9. 5. 1 , n o n -i nferi orit y i m plies t hat t he l o wer b o u n d o n t he t w o-si de d 9 6. 7 % 
c o nfi de nce i nter val o n t h e ser oc o n v ersi o n rat e a m o n g 1 2 t o < 1 8 -year -ol ds is wit hi n 1 0 perce nta ge 
p oi nts of t he a d ult rat e. Ma ki n g si milar ass u m pti o ns a b o ut t he tr ue ser oc o n versi o n rates i n t he 
ot her t w o p e diatric a ge c o h orts, a n d ass u mi n g t hat t he rat es i n t he t hree a g e c o h orts are i n de pe n d e nt 
of o ne a n ot her, t he o verall p o wer f or de m o nstrati n g t he n o n -i nferi orit y of all t hree a ge c o h orts is 
(9 3 . 3 %)3 = 8 1 %.  
T o meet t he o t her pri mar y o bjecti ve, t he l o wer b o u n d of t he t w o -si de d 9 8. 3 % c o nfi de nce i nter val 
o n t he  c o h ort-s p ecific ser oc o n versi o n rate m ust e q ual or e xcee d 7 0 % . U n der t he sa m e ass u m pti o ns 
as a b o ve –  i n p artic ular, ass u mi n g t he tr ue ser oc o n versi o n rat e wit hi n a n a ge c o h ort is at least 
9 2. 4 % –  1 4 3 e v al ua ble  vacci ne es pr o vi de greater t ha n 9 9. 9 % p o wer t o esta blis h t hat t he l o wer 
b o u n d o n t he c o h ort -s pecific rate is at least 7 0 %. P o wer is still greater t h a n 99. 9 % w he n re q uiri n g 
t he l o wer b o u n d o n all t hree c o h orts t o be 7 0 % or greater. 
T he o verall p o wer of me eti n g b ot h pri mar y o bjecti ves i n all t hree a g e c o h orts ca n b e a p pr o xi mat e d 
b y m ulti pl yi n g  t he p o wer of me eti n g t he n o n-i nf eri orit y o bjecti ve b y t h e p o wer of meeti n g t he 
7 0 % l o wer b o u n d o bje cti ve: 8 1 % x 9 9. 9 % ≈ 8 1 %. N ote t hat t he calc ulati o ns a b o ve rel y o n t h e 
ass u m pti o n t hat ser oc o n versi o n rate i n o ne c o h ort is c o m pletel y i n de pe n de nt of t he rate i n a n ot her. 
Si nce t hat ass u m pti o n is c o nser vati ve, it is li kel y t hat t he tr ue p o wer of t he trial is hi g her t ha n 8 1 %.  
Gi ve n  a t otal of 5 1 0 s u bjects recei ve V A X C H O R A , t here is a 9 9 % c h a nce t hat a n u nc o m m o n A E 
- o ne e x pecte d t o occ ur i n o nl y 1 % of vacci nees - will be o bser ve d at least o nce d uri n g t he trial.  
9. 2  
Tre at me nt Pe ri o d  
 
T he mai n st u d y c o nsists of a scree ni n g peri o d of 3 0 da ys, Da y 1 vacci nati o n, a n o bser vati o n peri o d 
fr o m Da y 1 t o Da y 2 9, a n d a f oll o w-u p peri o d t hr o u g h Da y 1 8 1. Place b o cr oss o ver has a n o pti o nal 
acti ve vacci nati o n at Da y 1 8 1 after u n bli n di n g, wit h a 6 m o nt h p ost v acci nati o n f oll o w -u p peri o d. 
C o h ort 1 has a n o pti o nal s u b -st u d y c o nsisti n g of a l o n g-ter m f oll o w-u p peri o d t hr o u g h Da y  7 3 0.  
9. 3  
Tre at me nt Gr o u ps  
•  S u bjects i n t he acti ve treat me nt gr o u p  i n eac h C o h ort at Da y 1 will recei ve V A X C H O R A . 
C o h ort 1:  1 2 t o < 1 8  years ( Acti ve treat me nt gr o u p: n = 1 5 0 ) 
C o h ort 2:  6 t o < 1 2  years ( Acti ve treat me nt gr o u p: n = 1 5 0 ) 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 5 0  of 6 1  
C o h ort 3:  2 t o  < 6  years ( Acti ve treat me nt gr o u p: n = 2 1 0 ) 
•  S u bjects i n t he P lace b o cr oss o ver gr o u p  i n eac h C o h ort at Da y 1 8 1  (± 7 ) will be offere d 
V A X C H O R A . 
C o h ort 1:  1 2 t o < 1 8  years ( Place b o cr oss o v er gr o u p: n = 2 5)  
C o h ort 2:  6 t o < 1 2  years ( Place b o cr oss o ver gr o u p: n = 2 5 ) 
C o h ort 3:  2 t o  < 6  years ( Place b o cr oss o ver gr o u p: n = 3 5)  
9. 4  
S afet y A n al ysis  
Safet y will be assesse d pri maril y t hr o u g h t he e val uati o n of s olicite d a n d u ns olicite d A Es .  
9. 4. 1  S olicite d A Es  
S olicite d A Es rec or de d d uri n g Da ys 1 -8  will be s u m marize d . S pecificall y, a ta ble will s u m marize 
t he perce nt of s u bjects wit hi n eac h treat me nt gr o u p w h o e x perie nce eac h s olicite d a d verse e ve nt 
at least o nce. A s ec o n d ta ble will prese nt a si milar s u m mar y c o nstrai ne d t o s olicite d A Es of 
m o derate se verit y or hi g her. A n a d diti o nal a nal ysis will prese nt t he mi ni m u m, me dia n a n d 
ma xi m u m n u m ber of d a ys t hat s u bjects i n eac h treat me nt gr o u p e x p erie n ce eac h t y p e of s olicite d 
A E. T he i nf or mati o n re g ar di n g t he i n ci de nce a n d se verit y of s olicite d A Es re p orte d b y Place b o 
cr oss o ver s u bjects bet wee n Da ys 1 8 1 a n d 1 8 8 will be s u m marize d a n d liste d. 
9. 4. 2  U ns olicite d A Es  
U ns olicite d A Es  rec or de d t hr o u g h Da y 2 9 will be s u m marize d b y treat me nt gr o u p, s yste m or ga n 
class, preferre d ter m a n d se verit y. U ns olicite d A Es c ollecte d fr o m Da ys 1 8 1 t o 2 0 9 will be 
s u m marize d se paratel y f or Place b o cr oss o ver s u bjects. 
S A Es rec or de d t hr o u g h Da y 1 8 1  or  Da y 3 6 5 (f or Place b o cr oss o ver s u bjects) or Da y 7 3 0 (f or s u b -
st u d y s u bjects) will be prese nte d.  
9. 5  
I m m u n o ge nicit y A n al ysis 
9. 5. 1  Pri m ar y I m m u n o ge nicit y A n al ys es  
Ser oc o n versi o n will be d efi ne d as a 4 -f ol d or greater rise i n S V A o v er Da y 1.  Eac h rate will be 
acc o m pa ni e d b y a 9 5 % c o nfi de nce i nter val ( CI) calc ulat e d usi n g t he 
Wils o n 
met h o d 
(A gresti  1 9 9 8 ).  
1.  T he ser oc o n versi o n rate bet wee n Da y 1 a n d Da y 1 1 f or vacci ne es i n eac h of t he 3 a ge 
c o h orts will be c o m pare d t o t he s er oc o n v ersi o n rat e f or vacci ne es bet w ee n t he a g es of 1 8 
a n d 4 5 w h o partici pate d i n t he l ot c o nsiste nc y st u d y P X V X -V C -2 0 0 -0 0 4 b y calc ulati n g t he 
differe n ce bet wee n t he t w o rates a n d c o m p uti n g a 9 6. 7 % c o nfi de nce i nt er val f or t his 
differe n ce.  
2.  F or eac h of t he 3 a g e c o h orts, t he pr o p orti o n of vacci nat e d s u bjects w h o e x perie n ce a 4 -
f ol d or greater i ncrease i n ser u m vi brioci dal titer bet wee n Da y 1 a n d Da y 1 1 will be 
calc ulate d, a n d a 9 8. 3 % c o nfi de n ce i nter val o n t his pr o p orti o n of ser oc o n verters will be 
c o m p ute d.  
Acce pt a nce Crit eri a f or Pri m ar y A n al yses 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 5 1  of 6 1  
1.  T he  l o wer b o u n d  of  t h e t w o-si de d 9 6. 7 %  c o nfi de nce  i nter val o n  t he differe nce  i n 
ser oc o n versi o n rates bet wee n c hil dre n  a n d a d ults  m ust  be  greater  t ha n -1 0  perce nta ge  
p oi nts.  
2.  T he  l o wer b o u n d  of  t he t w o-si de d 9 8. 3 %  c o nfi de n ce  i nter val o n  t he pr o p orti o n  of  vacci n ees  
w h o  ser oc o n vert bet wee n  Da y  1 a n d Da y  1 1  m ust  e q ual or  e xcee d 7 0 %.  
Al p h a -S pe n di n g Str ate g y  
I n or der  t o e ns ure t hat t he t otal T y pe I err or f or t he st u d y is ca p pe d at al p ha =  0. 0 5,  2/ 3  of  t he al p ha 
will  be  all otte d t o t he pri mar y  o bjecti ve  of  esta blis hi n g  n o n -i nferi orit y relati ve t o a d ults, a n d 1/ 3  of  
t he al p ha will be  all otte d t o t he pri mar y  o bjecti ve  of  de m o nstrati n g  t hat t he ser oc o n versi o n rate 
e q uals  or  e xcee ds  7 0 %.  T he  t w o pri mar y  o bjecti ves  will  be  e val uate d  i n de pe n de ntl y, a n d wit hi n  
eac h pri mar y  o bjecti ve,  testi n g i n t he differe nt  a ge c o h orts  will  pr ocee d  se q ue ntiall y be gi n ni n g  
wit h  t he data  f or t he 1 2  t o < 1 8  a ge c o h ort, as f oll o ws: 
1.  N o n -i nferi orit y: t he a nal ysis of n o n-i nferi orit y bet wee n vacci nees i n t he 1 2-1 8 a ge  c o h ort 
a n d a d ults bet wee n t h e a ges of 1 8 a n d 4 5 will be c o n d ucte d first. F or mal a nal ysis of n o n -
i nferi orit y i n t he 6 t o <1 2 a ge c o h ort will be perf or me d o nl y if t h e l o wer b o u n d of t he t w o -
si de d 9 6. 7 % c o nfi de nce i nter val o n t he differe n ce bet wee n t he ser oc o n versi o n rates f or 
c hil dre n i n t he 1 2 t o < 1 8 a ge c o h ort a n d a d ults e q uals or e xcee ds t h e pre -s pecifi e d 
acce pta nce criteri o n. F or mal e val uati o n of n o n -i nferi orit y i n t he 2 t o < 6 a ge c o h ort will 
occ ur o nl y if t he acce pta n ce criteri o n is met f or b ot h t he 1 2 t o < 1 8 a n d 6 t o < 1 2 a ge c o h orts. 
T his strate g y mai ntai ns t he o verall T y pe I err or f or t he pri mar y o bjecti ve of n o n -i nferi orit y 
at al p ha = 0. 0 3 3.  
2.  Ser oc o n versi o n Rate: t he a nal ysis of t he ser oc o n v ersi o n rate a m o n g vacci n ees i n t he 1 2 t o 
< 1 8 a ge c o h ort will be c o n d ucte d first. F or mal a nal ysis of t he acce pta bilit y of t he 
ser oc o n versi o n rate i n t he 6 t o < 1 2 a ge c o h ort will be perfor me d o nl y if t he l o wer b o u n d 
of t he t w o -si de d 9 8. 3 % c o nfi de nce i nter val o n t he ser oc o n versi o n rate i n t he 1 2 t o < 1 8 a ge 
c o h ort meets t h e pre -s pecifie d acce pta nce criteri o n. F or mal e val u ati o n of t h e acce pta bilit y 
of t he ser oc o n versi o n rate i n t he 2 t o < 6 a ge c o h ort will occ ur o nl y if t he acce pta nce 
criteri o n is met f or b ot h t he 1 2 t o < 1 8 a n d 6 t o < 1 2 a ge c o h orts. T his str ate g y mai ntai ns t he 
o verall T y p e I err or f or t he pri mar y o bj ecti ve  c o n cer ni n g t he ma g nit u de  of t he 
ser oc o n versi o n rate at al p ha = 0. 0 1 7. 
9. 5. 2  Se c o n d ar y A n al yses  
F or vacci nees i n t he a ge co h ort 1 2 t o < 1 8, t he p oi nt esti mate of t he ser oc o n versi o n rate f or 
vacci ne es as well as t h e c u m ulati ve ser oc o n versi o n rate  will be c o m p ute d  at t he ti me  p oi nts Da y 
2 9, Da y 9 1 a n d D a y 1 8 1, a n d a 9 5 % c o nfi de nce i nter val will be c o nstr ucte d f or eac h pr o p orti o n.   
P oi nt wise ser oc o n versi o n rates, c u m ulati ve s er oc o n versi o n rates, a n d c o nfi de nce i nter vals f or 
place b o reci pie nts i n t he a ge c o h ort 1 2 t o < 1 8 will be c o m p ute d at Da y 1 1, Da y 2 9, Da y 9 1 a n d 
Da y 1 8 1. F or vacci ne es  i n t he a ge co h orts 2 t o < 6 a n d 6 t o < 1 2, p oi nt wise a n d c u m ulati v e 
ser oc o n versi o n rat es a n d c orres p o n di n g c o nfi de nce i nter vals will be calc ulate d f or Da y 2 9.  
P oi nt wise ser oc o n versi o n rates, c u m ulati ve s er oc o n versi o n rates, a n d c o nfi de nce i nter vals f or 
pla ce b o reci pie nts i n t he a ge c o h orts 2 t o < 6 a n d 6 t o < 1 2 will be c o m p ute d at Da y 1 1 a n d Da y 2 9.   

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 5 2  of 6 1  
F or vacci ne es a n d pla ce b o reci pie nts i n t he a g e co h ort 1 2 t o < 1 8, t he G M T a n d 9 5 % c o nfi d e nce 
i nter val will be c o m p ute d f or Da y 1, Da y 1 1, Da y 2 9, Da y 9 1 a n d Day 1 8 1, a n d t he G M FI i n eac h 
treat me nt gr o u p will be calc ulate d f or Da y 1 1, Da y 2 9, Da y 9 1 a n d Da y 1 8 1.  F or vacci nees a n d 
place b o reci pie nts i n t he a ge co h orts 2 t o < 6 a n d 6 t o < 1 2, G M Ts a n d 9 5 % c o nfi de nce i nter vals 
will be calc ulate d f or D a y 1, Da y 1 1 a n d  Da y 2 9, a n d G M FIs a n d c orres p o n di n g c o nfi de nce 
i nter vals will be calc ulate d f or Da y 1 1 a n d Da y 2 9. F or partici pa nts i n t he s u b-st u d y, t he G M T a n d 
9 5 % c o nfi de nce i nter val a n d G M FI wit h 9 5 % c o nfi de nce i nter val will be calc ulate d f or Da ys 3 6 5, 
5 4 7 a n d 7 3 0. N u m ber of s u bjects wit h S V A titers less t ha n t he L L O Q will als o be s u m marize d f or 
eac h c ollecti o n ti me p oi nt.  
9. 5. 3  Me m or y B C ell C o nce ntr ati o n A n al yse s 
I n t he mai n st u d y, anti -O 1 L P S me m or y B cells will be assesse d at Da y 1 ( pri or t o vacci nati o n), at 
Da y 9 1,  D a y 1 8 1  f or a s u bset of s u bjects i n C o h ort 1 a n d at Da ys 3 6 5, 5 4 7, 7 3 0 f or s u bjects i n t he 
acti ve treat me nt  gr o u p of C o h ort 1 f or t he s u b st u d y. P oi nt esti mates of me dia n perce nta ge as well 
as me dia n f ol d rise Da y 1 t o D a y 9 1, Da y s 1 8 1, 3 6 5, 5 4 7, 7 3 0 will be pres e nte d.  
9. 6  
I nteri m A n al ysis 
After  t he last s u bjects e nr olle d i n Co h orts 1 a n d C o h ort 2 ha ve c o m plete d t heir Da y 1 8 1 visit, a 
preli mi nar y i m m u n o ge nicit y a n d safet y a nal ysis ma y be perf or me d a n d re p ort writte n t o facilitate 
a re g ulat or y s u b missi o n.  D ue t o t he u n bli n di n g of s u bjects i n di vi d uall y at Da y 1 8 1, t he s u bjects 
i n C o h orts 1 a n d 2 wi ll ha ve alrea d y bee n u n bli n d e d pri or t o t he a nal ysis a n d t he a nal ysis will n ot 
affect t he bli n d of t he C o h ort 3 s u bjects.  T h e  res ults of t hese a nal yses are n ot e x pecte d t o  alter t he 
c o urse of t he trial.  
 

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 5 3  of 6 1  
1 0  A D DI TI O N A L I N F O R M A TI O N  
1 0. 1  Et hic al C o n d uct of t he St u d y  
T he st u d y will be perf or me d i n acc or da nce wit h t he pr ot oc ol a n d c o nsiste nt wit h 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 l ocal re g ul at or y re q uire me nts a n d la ws.  
1 0. 2  I R B O versi g ht 
T he st u d y ( pr ot oc ol, i nf or me d c o ns e nt f or m, recr uiti n g ma terials, a n d a n y d oc u me nts see n b y t he 
s u bject) will be re vie we d a n d a p pr o ve d b y a n I R B a p pr o priate t o eac h st u d y site. S u bjects will n ot 
be recr uite d, c o ns e nte d, scree ne d, or e nr olle d u ntil  t he I R B has a p pr o ve d t he re q uire d 
d oc u me ntati o n. I n a d diti o n, t he  I R B will re vie w a me n d me nts t o  t he pr ot oc ol bef ore t heir 
i m ple me ntati o n. 
T he I n vesti gat or will retai n all c orres p o n de n ce wit h t he I R B i n t he  re g ulat or y bi n der a n d f or war d 
co pies of all I R B a p pr o vals t o t he S p o ns or.  
1 0. 3  I nf or me d C o nse nt a n d Asse nt  
T he S p o ns or will pr o vi de a master pare nt/ g uar di a n Inf or me d C o nse nt F or m ( I C F) te m plate t o eac h 
site f or d e vel o p me nt of a site-s p ecific p are nt/ g uar dia n I C F. T h e S p o ns or will als o pr o vi de 
i nf or me d asse nt f or m  (I A F) te m plates t o eac h site f or de vel o p me nt of site-s pecific a n d a g e-
a p pr o priate asse nt f or ms . 
All site -s pecific I C Fs a n d I A Fs m ust be a p pr o ve d  b y t he S p o ns or a n d t he I R B a n d m ust be i n 
c o m plia nce wit h I C H G C P, l ocal re g ulat or y re q uire me nts a n d le gal re q uire me nts. T he S p o ns or 
will a d vise t he Site of re q uire d c ha n ges  t o t he master I C F a n d I A F te m plat es d uri n g t he c o urse of 
t he st u d y. 
T he I n vesti ga t or will  e ns ure t hat eac h p ote ntial st u d y partici pa n t is f ull y i nf or me d a b o ut t he nat ure 
a n d o bjecti ves of t h e st u d y a n d p ossi ble ris ks ass ociate d wit h partici pati o n. Bef ore i nf or me d 
c o nse nt is o btai ne d, t he I n v esti gat or, or a q ualifi e d pers o n desi g n ate d b y t he i n vesti gat or, will  
pr o vi de t he p ote ntial st u d y partici pa n t wit h a m ple ti me a n d o p p ort u nit y t o i n q uire a b o ut t he d etails 
of t he trial, a n d will a ns wer all rele va nt q uesti o ns t o t he p ote ntial st u d y partici pa n t’s satisfacti o n. 
T he p ote ntial st u d y parti c i pa nt will t he n  deci d e w het her or n ot t o partici pate i n t he trial. T h e 
I n v esti gat or, or a q ualifie d pers o n desi g nate d b y t he I n vesti gat or, will o btai n writte n i nf or me d 
c o nse nt fr o m e ac h st u d y partici pa nt bef ore a n y st u d y -s pecific acti vit y is perf or me d.   
T he I n vesti gat or will retai n t he  ori gi nal a n d a n y a me n de d si g ne d a n d date d I C Fs a n d I A Fs at t he 
st u d y site a n d pr o vi de a c o p y t o eac h st u d y partici pa nt.  
1 0. 4  S u bject C o nfi de nti alit y  
T he I n vesti gat or will  e ns ure t hat eac h s u bject’s a n o n y mit y is mai ntai ne d. O n eC R Fs a n d  ot her 
d oc u me nts s u b mitte d t o t he S p o ns or a n d/ or its desi g nee, s u bjects m ust b e i de ntifie d b y s u bject 
n u m ber o nl y.   F or d oc u me nts t hat are n ot  f or s u b missi o n t o t he S p o ns or a n d/ or its desi g nee 
(e. g., si g ne d I C Fs), t he I n vesti gat or m ust mai ntai n t hese d oc u me nts sec urel y a n d i n c o m plia nce 
wit h Fe deral re g ul ati o ns a n d I C H G C P G ui deli ne s.  

P a x V a x, I nc.  
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 5 4  of 6 1  
1 0. 5  C o m pe ns ati o n f or I nj ur y  
T he S p o ns or will a d here t o l ocal re g ulati o ns a n d g ui deli nes re g ar di n g cli nical trial c o m p e nsati o n 
t o s u bjects w h ose healt h is a d versel y affecte d b y ta ki n g part i n t he st u d y. T he a p plica ble p olic y 
f or c o m pe nsati o n f or i njur y will be descri be d i n t h e master I C F te m plate.  
1 0. 6  Cli nic altri als. g o v  
F or p ur p oses of re p orti n g t o cli nicaltrials. g o v, t he S p o ns or is t he res p o nsi ble part y  a n d will pr o vi de 
i nf or mati o n re gar di n g t his st u d y i n acc or da n ce wit h a p plica ble re g ulati o ns. 
1 0. 7  P u blic Discl os ure a n d P u blic ati o n P olic y  
All p u blicati o n ri g hts are deli neate d i n t he Cli nical St u d y A gree me nt.  S p o ns or or its desi g ne e s hall 
ha ve t he ri g ht t o p u blis h o r ot her wis e p u blicl y dis cl ose t he i nf or mati o n c o ntai ne d i n or relate d t o 
t he St u d y Vacci ne, t he St u d y Data, or ot her C o nfi de ntial I nf or mati o n i n a n y f or m wit h o ut t he 
writte n c o nse nt of Site, t he Pri nci pal I n vesti gat or or a n y ot her pers o n. Eac h of t he Site s a n d t he 
Pri nci pal I n v esti gat or f urt her a grees t hat S p o ns or s hall ha ve t he e x cl usi ve ri g ht t o c o m mercialize 
a n y pr o d ucts or ser vices t hat are base d u p o n, or deri ve d fr o m t he St u d y Vacci ne, t he St u d y Data, 
or ot her C o nfi de ntial I nf or mati o n.  
1 0. 8  A me n d me nts  
T he p r ot oc ol ma y be a me n de d o nl y b y t he S p o ns or. A gree me nt fr o m t he I n v esti gat or m ust be 
o btai ne d f or all pr ot oc ol a me n d me nts a n d a me n d me nts t o t he I nf or me d C o nse nt d oc u me nt.  T h e 
I R B m ust ge nerall y be i nf or me d of all a me n d m e nts  pri or t o i m ple me ntati o n. I n a d diti o n, t he 
I n v esti gat or m ust o btai n I R B a p pr o val f or a n y a me n d me nts li kel y t o affect t he safet y of st u d y 
partici pa nts pri or t o i m ple me ntati o n .  
T he I n vesti gat or or S p o ns or ma y i m ple me nt a n a me n d me nt pri or t o I R B n otificati o n  or a p pr o val 
o nl y i n or der t o eli mi nate a n a p pare nt i m me diate hazar d t o st u d y partici pa nts. I n t hat e ve nt, t he 
I n v esti gat or m ust n otif y t he I R B a n d S p o ns or i n writi n g wit hi n 7 cale n dar d a ys after t he 
i m ple me ntati o n. A me n d me nts, i ncl u di n g descri pti o ns a n d rati o nales, will be d oc u me nte d i n t his 
secti o n of t he pr ot oc ol. T he I n vesti gat or m ust se n d a c o p y of t h e a p pr o val letter fr o m t h e I R B t o 
Pa x Va x ( or its desi g ne e).  
1 0. 9  A n n u al Pr o gress Re p ort  
Pa x Va x will s u b mit a s u m mar y of t he pr o gress of t he trial t o t he I N D o n  file wit h t he F D A o n ce a 
year. I n a d diti o n, t he I n v esti gat or is res p o nsi ble f or s u b mitti n g pr o gress re p orts at least a n n uall y 
t o t he I R B a n d I B C t hat a p pr o ve d t he st u d y. I nf or mati o n will be pr o vi de d o n t he dat e of i ncl usi o n 
of t he first s u bject, n u m bers o f s u bjects i ncl u de d a n d n u m bers of s u bjects t hat ha ve c o m plete d t h e 
trial, S A Es a n d seri o us a d verse reacti o ns, ot her pr o ble ms, a n d a me n d me nts. 
1 0. 1 0   E n d of St u d y Re p ort  
T he I n vesti gat or will n otif y t heir I R B a n d I B C of t he e n d of t h e st u d y a n d will s u b mit a fi nal re p ort 
usi n g t he f or ms a n d/ or f or mat s pecifie d. T h e e n d of t he st u d y is defi ne d as t he last s u bject’s last 
visit. I n cas e t he st u d y is e n de d pre mat urel y, t he I n v esti gat or will n otif y t he I R B a n d I B C, 
i ncl u di n g t he reas o ns f or t he pre mat ure ter mi nati o n. 

 
P a x V a x, I nc.  
 
St u d y  Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 5 8  of 6 1  
A P P E N DI X B: T O XI CI T Y G R A DI N G S C A L E  
T a ble f or Cli nic al A b n or m alities   
V A C CI N E 
R E A C TI O N  
MI L D ( Gr a de 1)  
M O D E R A T E ( Gr a de 2)  
S E V E R E ( Gr a de 3)  
P O T E N TI A L L Y LI F E 
T H R E A T E NI N G ( Gr a de 
4)  
A b d o mi nal Pai n  
Mil d, n o i nterfere nce wit h 
acti vit y 
S o me i nterfere nce wit h 
acti vit y 
Si g nifica nt, pre ve nts dail y 
acti vit y 
E R visit or h os pitalizati o n 
f or h y p ote nsi ve s h oc k 
A n ore xia  
( Lac k 
of 
a p petite) 
N o i nterfere nce wit h 
acti vit y 
S o me i nterfere nce wit h 
acti vit y 
Si g nifica nt, pre ve nts dail y 
acti vit y 
E R visit or h os pitalizati o n  
Diarr hea  
4  l o ose st o ols / 2 4 h o urs 
5 l o ose st o ols/ 2 4 h o urs  
>  6 l o ose st o ols/ 2 4 h o urs  
E R visit or h os pitalizati o n  
Fati g ue  ( Tire d ness) 
Mil d, n o i nterfere nce wit h 
acti vit y 
S o me i nterfere nce wit h 
acti vit y 
Si g nifica nt, pre ve nts dail y 
acti vit y 
E R visit or h os pitalizati o n  
Fe ver   
> 1 0 0. 4 –  1 0 1. 1° F  
( 3 8. 0 – 3 8. 4° C)  
> 1 0 1. 2 –  1 0 2° F  
( 3 8. 5 – 3 8. 9° C)  
>  1 0 2. 1° F – 1 0 4° F  
( 3 9° C – 4 0° C)  
> 1 0 4° F  
( > 4 0° C) 
Hea dac he  
Mil d, n o i nterfere nce wit h 
acti vit y 
S o me i nterfere nce wit h 
acti vit y 
Si g nifica nt, pre ve nts dail y 
acti vit y 
E R visit or h os pitalizati o n  
M yal gia  
Mil d, n o i nterfere nce wit h 
acti vit y 
S o me i nterfere nce wit h 
acti vit y 
Si g nifica nt, pre ve nts dail y 
acti vit y 
E R visit or h os pitalizati o n  
Na usea  
Mil d, n o i nterfere nce wit h 
acti vit y 
S o me i nterfere nce wit h 
acti vit y 
Si g nifica nt, pre ve nts dail y 
acti vit y 
E R visit or h os pitalizati o n 
f or h y p ote nsi ve s h oc k 
V o miti n g  
1 – 2 e pis o des/ 2 4 h o urs  
> 2 e pis o des/ 2 4 h o urs  
Re q uires I V h y drati o n  
E R visit or h os pitalizati o n 
f or h y p ote nsi ve s h oc k "  
W he n d e vel o pi n g t his T o xicit y Gra di n g Scale, Pa x Va x referre d t o t he rec o m me n dati o ns i n t he F D A’s G ui da nce f or I n d ustr y: T o xic it y 
Gra di n g Scale f or H ealt h y A d ult a n d A d olesce nt S u bjects E nr olle d i n Pre ve nti ve Vacci ne Cli nical Trials ( U S F D A 2 0 0 7 ). 
Diarr hea 1 -3 St o ols/ 2 4 h o urs: Rec or d as “l o ose st o ols” o n t he  A E C R F.  
 
 

 
P a x V a x, I nc.  
 
 
St u d y Pr ot oc ol: P X V X -V C -2 0 0 -0 0 6  
 
 
V 3. 0 2 0 1 7 1 1 1 5  
C O N FI D E N TI A L  
P a ge 5 9  of 6 1  
R E F E R E N C E S  
A gresti  A , C o ull BA. ( 1 9 9 8). A p pr o xi mate is better t ha n “e xact” f or i nter val esti mati o n of 
bi n o mial pr o p orti o ns. T he A meric a n Statisticia n, 5 2( 2), 1 1 9 -1 2 6.  
Ali M, Nels o n  A,   L o p ez  A L, Sac k  D A. ( 2 0 1 5) U p date d Gl o bal B ur de n of C h olera i n E n d e mic 
C o u ntries. Pl o S  Ne gl Tr o p Dis. 2 0 1 5 J u n 9( 6):  e 0 0 0 3 8 3 2.  
C o o per PJ, C hic o M E, L os o ns k y G, Sa n d o val C, Es pi nel I, Sri d hara R, A g uilar M, G ue vara 
A, G u deria n R H, Le vi ne M M, Griffi n G E, N ut m a n T B: Al be n daz ol e Treat me n t of C hil dre n 
wit h Ascariasis E n ha n ces t he Vi bri oci dal A nti b o d y Res p o nse t o t he Li ve Atte n uate d Oral 
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