Vaccine 33 (2015) 6360–6365

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Vaccine
journal homepage: www.elsevier.com/locate/vaccine

A randomized, non-inferiority trial comparing two bivalent killed,

whole cell, oral cholera vaccines (Euvichol vs Shanchol) in the
Philippines
Yeong Ok Baik a,h,1 , Seuk Keun Choi a,h,1 , Remigio M. Olveda b , Roberto A. Espos c ,
Antonio D. Ligsay d , May B. Montellano e , Jong Sun Yeam a , Jae Seung Yang f , Ju Yeon Park g ,
Deok Ryun Kim g , Sachin N. Desai g , Ajit Pal Singh g , Ick Young Kim h , Chan Wha Kim h ,
Sue-nie Park a,∗
a
EuBiologics Co., Ltd., Seoul, Republic of Korea
b
Research Institute for Tropical Medicine, Muntinlupa City, Philippines
c
De Lasalle University Medical Center, Dasmarinas, Philippines
d
National Children’s Hospital, Quezon, Philippines
e
Mary Chiles General Hospital, Manila, Philippines
f
Clinical Immunology, Laboratory Science Unit, International Vaccine Institute (IVI), Seoul, Republic of Korea
g
Development and Delivery, International Vaccine Institute (IVI), Seoul, Republic of Korea
h
Department of Biotechnology, Korea University, Seoul, Republic of Korea

a r t i c l e i n f o a b s t r a c t

Article history: Background: Currently, there are two oral cholera vaccines (OCV) that are prequalified by the World Health
Received 28 May 2015 Organization. Both (Dukoral and Shanchol) have been proven to be safe, immunogenic, and effective. As
Received in revised form 27 July 2015 the global supply of OCV remains limited, we assessed the safety and immunogenicity of a new low cost,
Accepted 28 August 2015
killed, bivalent OCV (Euvichol) in the Philippines.
Available online 5 September 2015
Methods: The randomized controlled trial was carried out in healthy Filipino adults and children. Two
doses of either the current WHO prequalified OCV (Shanchol) or the same composition OCV being con-
Keywords:
sidered for WHO prequalification (Euvichol) were administered to participants.
Oral cholera vaccine
Safety
Results: The pivotal study was conducted in total of 1263 healthy participants (777 adults and 486 chil-
Immunogenicity dren). No serious adverse reactions were elicited in either vaccine groups. Vibriocidal antibody responses
Euvichol to V. cholerae O1 Inaba following administration of two doses of Euvichol were non-inferior to those of
Shanchol Shanchol in adults (82% vs 76%) and children (87% vs 89%). Similar findings were observed for O1 Ogawa
Children in adults (80% vs 74%) and children (91% vs 88%).
Adults Conclusion: A two dose schedule with Euvichol induces a strong vibriocidal response comparable to those
elicited by the currently WHO prequalified OCV, Shanchol. Euvichol will be an oral cholera vaccine suitable
for use in lower income countries, where cholera still has a significant economic and public health impact.
© 2015 Elsevier Ltd. All rights reserved.

1. Introduction
Cholera is a rapidly dehydrating diarrheal disease, which is pre-
ventable and treatable. It has a disease case burden of 2.8 million
and kills approximately 100,000 people each year [1]. Prolonged
and frequent outbreaks can be devastating and dramatically impact
∗ Corresponding author. Tel.: +82 2 572 6675; fax: +82 507 891 2537.
E-mail addresses: suenie@eubiologics.com, sunnypark54@hanmail.net
(S.-n. Park).
1
These authors contributed equally to this work.
many countries throughout the Asian, African, and in Haiti and the
Dominican Republic. Improvements to water quality, sanitation,
and hygiene are mainstays of cholera prevention, but continue to be
goals far out of reach for many affected countries. Safe and effective
oral cholera vaccines (OCV) have been available since the mid-
1980s, but have not been widely used due to concerns over low
vaccine production capacity and possible diversion of traditional
prevention and control efforts.
Considerable progress has been made during the last decade
in the development of OCV. After technology was transferred for
an efficacious, killed OCV from Sweden, the Vietnamese govern-
ment used a local manufacturer to license and produce OCV for

http://dx.doi.org/10.1016/j.vaccine.2015.08.075
0264-410X/© 2015 Elsevier Ltd. All rights reserved.
 Y.O. Baik et al. / Vaccine 33 (2015) 6360–6365
use in its public health programs. With the goal of accelerat-
ing global use of this vaccine, the International Vaccine Institute
(IVI), in cooperation with a Vietnamese manufacturer, worked to
improve the production process and transferred that technology
to an Indian manufacturer (Shantha Biotechnics Ltd., Hyderabad,
India). Shantha produced Shanchol and obtained the licensure in
2009. Shanchol, which was prequalified by WHO in 2011, demon-
strated immunogenicity and efficacy in endemic settings [2–4],
which has enabled easier purchase by UN agencies for areas at risk.
Two of the key benefits of this vaccine are its lower price and no
need for co-administration of a buffer, reducing the logistical hur-
dles of OCV administration, as demonstrated in recent vaccination
campaigns taking place in Bangladesh, India, Haiti, South Sudan,
Ethiopia, and Guinea [5]. In view of the increasing numbers of large
and protracted outbreaks, the 64th World Health Assembly recom-
mended the use of OCV “where appropriate, in conjunction with
other recommended prevention and control methods” [6]. Through
technology transfer from IVI and support by the Global Health
Investment Fund, EuBiologics Co., Ltd. (Seoul, Korea) is working
to increase the availability of a second low cost OCV (Euvichol) to
resource limited settings. In a phase I clinical trial of Euvichol in
20 healthy adult males in Korea, no clinically relevant safety issue
is observed and 95% (19/20) participants demonstrated a four-fold
rise in Vibrio cholerae O1 antibodies following a two-dose schedule
given two weeks apart [7]. With recent report by GAVI to launch
a 20 million dose global stockpile by 2018 [8], increasing global
production and availability has become a global priority. In order
to address limited supply concerns, we assessed the safety and
immunogenicity of Euvichol as compared to its predecessor, Shan-
chol in a randomized controlled trial in the Philippines, a country
where cholera has affected several provinces [9].
2. Materials and methods
2.1. Participants, study sites, and ethical considerations
The study was conducted at four clinical trial sites in greater
Manila: Research Institute for Tropical Medicine, De La Salle
Health Sciences Institute, National Children’s Hospital, and Mary
Chiles General Hospital. Healthy adults (18–40 years) and chil-
dren (1–17 years) were recruited. Exclusion criteria included
immune deficiency, severe chronic disease, active fever, general-
ized gastrointestinal symptoms within 24 h prior to enrolment,
diarrhea/abdominal pain for at least two weeks within 6 months of
study initiation, administration of antidiarrheals and/or antibiotics
within the past week, pregnant and lactating women, or receipt of
any vaccine within the week prior to enrolment. Written informed
consent was obtained from all adults and parents of participating
children prior to enrolment. The trial protocol was approved by
the institutional review boards of The Philippines Food and Drug
Administration, IVI, and study sites. The study was monitored by
both an independent local study monitoring organization and an
external clinical research organization. The trial was registered on
www.clinicaltrials.gov (NCT02164110).
2.2. Study design, randomization, and blinding
This was an individually randomized controlled, multi-center,
non-inferiority trial in healthy adults (aged 18–40 years) and
children (aged 1–17 years) randomized into two groups to receive
two oral doses of either: a new killed bivalent (O1 and O139
serogroups) whole cell-oral cholera vaccine (Euvichol) or the cur-
rently WHO prequalified killed bivalent (O1 and O139 serogroups)
OCV (Shanchol). Randomization was stratified among adults and
children. Subjects were randomized to receive the investigational
(Euvichol) or comparator (Shanchol) vaccine using a pre-generated
6361
randomization table. Randomization was performed by the inves-
tigator for individuals meeting eligibility, after which the assigned
study agent was dispensed by the trial pharmacist. Block random-
ization was used by each study site to ensure that participants
are allocated equally in two groups. The SAS Proc plan procedure
was used for randomization code generation. The sponsor and
principal investigators held sealed copies of the randomization
list, which was not opened until all data for analysis had been
locked. Because the aluminum caps of the two vaccines are easily
distinguishable, a double blind design was not appropriate. Hence,
vaccinators were appointed separately to administer the study
agents to all participants. All clinical investigators and laboratory
staff assigned to evaluate immunogenicity and safety outcomes
remained blinded. Participants were informed they would receive
one of two OCVs, but remained blinded to the allocation.
2.3. Study procedure
Both vaccines contain the same killed cells of V. cholerae,
undergo similar manufacturing processes, and are presented in
glass vials. Each dose of Euvichol or Shanchol contains 300
Lipopolysaccharide ELISA Unit (LEU) of V. cholerae O1 Inaba Cairo
48 (Heat inactivation), 600 LEU of V. cholerae O1 Inaba Phil 6973
El Tor (Formalin inactivation), 300 LEU of V. cholerae O1 Ogawa
Cairo 50 (Formalin inactivation), 300 LEU of V. cholerae O1 Ogawa
Cairo 50 (Heat inactivation), and 600 LEU of V. cholerae O139 4260B
(Formalin inactivation). Following the informed consent, demo-
graphic information, medical history, physical examination, and
confirmation of all inclusion/exclusion criteria were recorded for
all potential participants. Urine pregnancy tests were performed at
screening in all women of childbearing age.
Participants were randomized 1:1 to receive either two doses of
Euvichol or Shanchol vaccine, given 14 days apart, and instructed
not to eat 1 h before or after dosing. All study agents were stored at
2–8 ◦ C before administration. After proper shaking and inspection
of the vial, a designated member of the study team adminis-
tered the 1.5 ml dose of study agent by oral syringe, followed
by offering the participant a small cup of water. All participants
were observed for 30 min following dosing and given diaries to
record any solicited adverse events occurring up to 6 days fol-
lowing either dose. Concomitant medications, unsolicited adverse
events, and serious adverse events were collected from day 0 to
day 28. Hematology, chemistry, and urinalysis laboratory testing
were performed on day 0 and 28 for participants who have been
given at least 1 dose of Euvichol or Shanchol (624 and 632 partici-
pants received Euvichol and Shanchol, respectively) to monitor for
any clinically significant changes. Blood samples for serology were
obtained immediately prior to first dosing on day 0, before second
dosing on day 14, and on day 28 (14 days following second dose).
Serum samples were stored at −60 ◦ C and shipped to the Inter-
national Vaccine Institute, where vibriocidal antibody assays were
performed.
2.4. Outcomes
We compared the safety and immunogenicity of Euvichol
compared to Shanchol. The primary endpoint for safety was the
proportion of participants experiencing adverse events during
six days after either dose or unsolicited/serious adverse events
within 28 days after first dose. For immunogenicity, our primary
endpoint was the proportion of subjects exhibiting seroconversion,
defined as a four-fold or greater rise in titers of serum vibriocidal
antibodies in the fourteen days after the second dose to O1 Inaba
and Ogawa relative to that measured at day 0 as baseline [7].
Secondary endpoints for immunogenicity included geometric
mean titers to O1 Inaba, O1 Ogawa and O139, as well as vibriocidal
6362 Y.O. Baik et al. / Vaccine 33 (2015) 6360–6365

antibody response (seroconversion) to O139 following the second 3. Results

dose of study agents.
2.5. Statistical analyses
Sample size calculations were based on the non-inferiority of
seroconversion rates in Euvichol recipients compared to those of
Shanchol recipients. We assumed 83.5% seroconversion in chil-
dren and 66.2% in adults after two doses based on previous results
obtained from Shanchol [2,10–12]. If the difference between sero-
conversion rates in Euvichol recipients compared to Shanchol
recipients was no less than 10%, Euvichol would be considered to be
non-inferior. Assuming a two-tailed ␣ of 5%, 80% power, and a 10%
drop-out rate, a total of 482 children and 782 adults were targeted.
All analyses were performed using SAS 9.3 (SAS Institute, Cary
NC). Analyses for comparisons of dichotomous outcomes such as
adverse events and seroconversion were performed with the chi-
square test or Fisher’s exact test. For comparisons of vibriocidal
titers, the Student’s t-test was performed using the pooled or
Satterthwaite method depending on whether the variances were
equal or not [13]. For the primary endpoint of immunogenicity
non-inferiority was evaluated by calculating the difference in sero-
conversion rates between Euvichol and Shanchol from baseline to
14 days after the second dose. The lower boundary of 95% confi-
dence interval was evaluated using clinically acceptable margin of
10% [14]. Other comparisons were two-tailed and all data from trial
volunteers used for analysis were anonymized.
3.1. Populations analyzed
The enrolment and evaluation of subjects for safety and
immunogenicity is shown in the study flow chat (Fig. 1). The study
cohort consisted of 1263 participants (777 adults aged ≥18 years,
486 children aged 1–17 years), who were recruited from May to
September 2014. For safety, intention to vaccinate analysis was per-
formed, which included all participants randomized in the study
and who received one or more dose of either vaccine (777 adults
and 484 children were included in this analysis). For immunogenic-
ity, per protocol analysis was performed on randomized, eligible
subjects, who received 2 doses of the assigned vaccine and were
present for all study visits (Vibriocidal analysis of O1 Inaba/Ogawa
and O139: 753 adults and 466 children). Characteristics of partic-
ipants in each vaccine group are shown in Table 1. There were no
significant differences in age breakdown or male to female ratio of
those who received either vaccine within adult or child groups.
3.2. Adverse events
The safety cohort comprised 1261 participants. No significant
difference in the number of participants with solicited adverse
events (AE) were observed between the Euvichol (E) and Shanchol
(S) vaccine groups in adults (E: 17/388, 4.4% vs S: 27/389, 6.9%,
p = 0.12) and children (E: 12/240, 5% vs S: 17/244, 7%, p = 0.36).

Clinical evaluation of adults (n=794) and children (n=487)

for eligibility

17 participants excluded due to

• Diarrhea/abdominal pain (n=2)
Randomization • Pregnancy/lactation (n=3)
• Clinical judgement (n=10)
• Vaccinated within 1week (n=2)

Enrolled Subject a
• Adults (n=777)
• Children (n= 486)

Received Euvichol dose 1 at Day 0 b Received Shanchol dose 1 at Day 0 b

For safety data analysis
• Adults (n=388) • Adults (n=389)
• Children (n=240) • Children (n=244)

Provided blood specimen and Provided blood specimen and

received Euvichol dose 1 at Day 0 c received Shanchol dose 1 at Day 0 c
• Adults (n=387) • Adults (n=388)
• Children (n=237) • Children (n=244)

Provided blood specimen and Provided blood specimen and

received Euvichol dose 2 at Day 14 d received Shanchol dose 2 at Day 14 d
• Adults (n=381) • Adults (n=376)
• Children (n=232) • Children (n=235)

For
Provided blood specimen at Day 28 e Immunogenicity analysis Provided blood specimen at Day 28
• Adults (n=377) • Adults (n=376)
• Children (n=231) • Children (n=235)

Fig. 1. CONSORT study flow diagram. Note: (a) Excluded 1 subject due to subject duplication. (b) Excluded 2 children (1 for Euvichol (E), 1 for Shanchol (S)) due to inadequate
blood sample. (c) Excluded 2 adults (1 for E, 1 for S) due to inadequate blood sample and clinical screen failure and 3 children (E) due to inadequate blood sample. (d) Excluded 18
adults (6 for E, 12 for S) because of withdrawal, loss to follow up, clinical screen failure, inadequate blood sample and 14 children (5 for E, 9 for S) due to withdrawal, inadequate
blood sample and loss to follow up. (e) Excluded 4 adults (E) because of the withdrawal, inadequate blood sample and loss to follow up and 1 child (E) due to withdrawal.
 Y.O. Baik et al. / Vaccine 33 (2015) 6360–6365 6363

Table 1
Demographic characteristics.

Characteristics Adults Children

Euvichol (n = 388) Shanchol (n = 389) p-Value Euvichol (n = 240) Shanchol (n = 244) p-Value

Gender
Male (%) 186 (47.9) 174 (44.7) 0.37 127 (52.9) 112 (45.9) 0.12
Female (%) 202 (52.1) 215 (55.3) 113 (47.1) 132 (54.1)

Age (years)
Mean (SD) 27.6 (6.5) 28.3 (6.4) 0.13 8.6 (4.7) 8.4 (4.7) 0.64
Median 27 (18, 40) 28 (18, 40) 9 (1, 17) 8 (1, 17)

A total of 44 adults (5.7%) and 29 children (6.0%) were reported information on the clinical efficacy of Euvichol. Moreover, in
to have adverse events within six days of either dose. The most our study, Serum anti O1 Inaba and Ogawa vibriocidal antibody
commonly reported solicited AEs reported were headaches (2.9%) responses were comparable for both vaccines in the Philippines
and fever (1%), with less overall solicited AEs in the Euvichol group cohort. Geometric fold rise (∼27, 15, and 30-fold rise) and serocon-
observed within six days of either dose (Table 2). No serious adverse version (∼90%, 80%, and 80%) of these OCVs were markedly elevated
events were observed throughout the study period.
Table 2
Solicited systematic adverse events (AEs) among adults and children.
3.3. Vibriocidal antibody response
Euvichol Shanchol p-Value
A per protocol analysis was conducted for immunogenicity data Adults
on a total of 1219 participants, who completed all study visits. Within 6 days of first dose (n = 388) (n = 389)
Immune responses to V. cholerae O1 Inaba and O1 Ogawa follow- Nausea/vomiting 0 0
Diarrhea 1 2 1.00
ing administration of two doses of Euvichol were non-inferior to
Headache 9 14 0.29
those of Shanchol, as the difference measured was greater than the Fatigue 0 0
pre-defined cut-off value of −10%. Geometric mean titers (GMT), Myalgia 2 1 0.62
geometric mean fold rise (GMFr), and seroconversion rates are dis- Fevera 2 6 0.29
played in Table 3 Among vaccine recipients, the baseline GMTs Loss of appetite 0 0

(Euvichol vs Shanchol) to V. cholerae were identical in adults (E: Within 6 days of second (n = 382) (n = 377)
35.8 vs S: 35.8, p = 0.99) and similar in children (E: 12.3 vs S: 11.9, dose
Nausea/vomiting 0 1 0.50
p = 0.88). In V. cholerae O1 Inaba, seroconversion rates of Euvichol
Diarrhea 0 1 0.50
were non-inferior to those of Shanchol in adults (E: 81.7 vs S: 76.3, Headache 6 7 0.79
p = 0.07) and children (E: 87.4 vs S: 88.9, p = 0.62). Furthermore, Fatigue 0 0
when we analyzed seroconversion rate data closely, high rates of Myalgia 0 1 0.50
seroconversion were also maintained in the youngest age groups Fevera 2 1 1.00
Loss of appetite 0 0
(1–5 years old) from both vaccine groups (E: 80.6 vs S: 83.8, p = 0.61,
Table S1). Number (%) of participants 17(4.4) 27(6.9) 0.12
Both vaccines induced a strong immune response against with ≥ 1 AEs within 14
daysb of either dose
O1 Ogawa, though statistically higher seroconversion rates were Number (%) of participants 0 0
observed in adult Euvichol recipients (E: 80.1 vs S: 73.9, p = 0.04). with SAEs within 14 days
Seroconversion rates in children to O1 Ogawa showed no signifi- of either dose
cant difference between vaccine groups (E: 90.5 vs S: 88.1, p = 0.40).
Immune responses to V. cholerae O139 were less pronounced for Euvichol Shanchol p-Value

both vaccines. Results regarding non-inferiority for O139 are incon- Children
clusive since the 95% confidence interval lower bound value was Within 6 days of first dose (n = 240) (n = 244)
Nausea/vomiting 1 0 0.50
below the clinical margin (<−10%).
Diarrhea 1 1 1.00
Headache 0 3 0.25
4. Discussion Fatigue 0 0
Myalgia 0 0
Fevera 3 5 0.72
The data suggests that a two dose schedule with the new killed
Loss of appetite 0 0
bivalent OCV, Euvichol, induces a strong vibriocidal responses,
comparable to those elicited by the currently WHO prequalified Within 6 days of second dose (n = 235) (n = 237)
Nausea/vomiting 2 2 1.00
OCV, Shanchol. Important differences and benefits of the newer Diarrhea 0 2 0.50
generation killed bivalent oral cholera vaccines compared to earlier Headache 2 3 1.00
first generation oral cholera vaccine (Dukoral) are their lower man- Fatigue 0 0
ufacturing cost and no need for buffer or water co-administration, Myalgia 0 0
Fevera 5 9 0.29
resulting in a decreased storage space requirement. Safety has
Loss of appetite 0 0
been established in Shanchol, with approximately 2 million doses
administered since it became licensed in 2009. In this study, Euvi- Number (%) of participants 12 (5.0) 17 (7.0) 0.36
with ≥ 1 AEs within 14 daysb
chol also did not give rise to any safety concerns.
of either dose
While measuring the vibriocidal antibodies in subjects admin- Number (%) of participants 0 0
istered with Euvichol is an indirect approach of determining the with SAEs within 14 days of
protection against V. cholerae, the interpretation of the findings either dose
obtained in this study alongside the existing immunogenicity and a
Temperature ≥ 38.0 ◦ C.
b
clinical efficacy data of Shanchol could be regarded as bridging Number of participants of 6 days is the same as that of 14days.
6364 Y.O. Baik et al. / Vaccine 33 (2015) 6360–6365

Table 3
Vibriocidal antibody titers and proportion of ≥4-fold rise from baseline GMT to V. cholerae (O1 Inaba, O1 Ogawa, and O139).

Adults (≥18 years old) O1 Inaba O1 Ogawa O139

Euvichol Shanchol p-Value Euvichol Shanchol p-Value Euvichol Shanchol p-Value

(n = 377) (n = 376) (n = 377) (n = 376) (n = 377) (n = 376)

Day 0
Baseline GMTa 35.8 35.8 0.99 76.8 73.8 0.82 4.3 3.4 0.08

Day 14
GMTa 1140 1086 0.68 1718 1280 0.01 16.1 17.9 0.52
GMFrb 31.9 30.3 0.77 22.4 17.4 0.09 3.8 5.3 0.02
# seroconversion (%)c 317 (84.1) 315 (83.8) 0.91 322 (85.4) 295 (78.5) 0.01 127(33.7) 157 (41.8) 0.02
95% CI lower boundaryd −4.94% 1.48% −14.97%

Day 28
GMTa 773 732 0.59 1238 962 0.01 12.4 14.0 0.42
GMFrb 21.6 20.5 0.73 16.1 13.0 0.15 2.9 4.2 0.01
# seroconversion (%)c 308 (81.7) 287 (76.3) 0.07 302 (80.1) 278 (73.9) 0.04 108(28.6) 142 (37.8) 0.01
95% CI lower boundaryd −0.44% 0.18% −15.82%

Children (1–17 years old) O1 Inaba O1 Ogawa O139

Shanchol Shanchol p-Value Shanchol Shanchol p-Value Euvichol Shanchol p-Value

(n = 231) (n = 235) (n = 231) (n = 235) (n = 231) (n = 235)

Day 0
Baseline GMTa 12.3 11.9 0.88 12.8 12.9 0.96 4.0 3.0 0.09

Day 14
GMTa 680 609 0.63 780 636 0.35 60.1 65.7 0.62
GMFrb 55.1 51.0 0.75 61.0 49.2 0.39 15.1 22.0 0.07
# seroconversion (%)c 198 (85.7) 198 (84.3) 0.66 200 (86.6) 197 (83.8) 0.40 148(64.1) 158(67.2) 0.47
95% CI lower boundaryd −5.03% −3.69% −11.78%

Day 28
GMTa 625 621 0.98 838 733 0.42 40.0 43.2 0.68
GMFrb 50.6 52.1 0.90 65.6 56.7 0.51 10.0 14.5 0.07
# seroconversion (%)c 202 (87.4) 209 (88.9) 0.62 209 (90.5) 207 (88.1) 0.40 131(56.7) 146(62.1) 0.23
95% CI lower boundaryd −7.35% −3.22% −14.32%
a
Geometric mean reciprocal titers.
b
Geometric mean-fold rise from baseline to 14 days after first dose or from baseline to 14 days after second dose.
c
# with ≥4-fold rise in titers from baseline to 14 days after first dose or from baseline to 14 days after second dose.
d
95% lower confidence intervals for noninferiority analysis of the difference and the margin is 10% difference is seroconversion rate of (Euvichol-Shanchol).

in Vietnam, Ethiopia and Philippines, respectively, all regions with
low cholera endemicity ([10,15] and this study). A robust immuno-
logic response to Euvichol was also found among both children
and adults. Because our study population in the Philippines has
less exposure and boosting by naturally occurring vibrios, it is pre-
sumed that they may also exhibit a lower pre-existing immunity. It
would be difficult to extrapolate clinical protection offered by the
vaccine in cholera endemic areas. Since young children (1–5 years),
who likely experience less environmental exposure to V. cholerae,
exhibited lower vibriocidal responses than older group, it may be
possible that some degree of memory B cell response following
natural cholera infection could generate an anamnestic response
in adults. Indeed, children immunized with cholera vaccine have
shown significantly lower cholera-specific memory responses than
individuals who had been naturally infected with pathogen [16].
Yet, since Euvichol is a killed bivalent OCV with identical strain
composition and a similar manufacturing process to Shanchol, this
non-inferiority trial can serve as an evidence for policy makers to
support its use as a complement to the present vaccines.
The WHO has recommended pre-emptive use of OCV in emer-
gency situations and the formation of an initial OCV stockpile since
1999 [17]. These recommendations have not been adopted for
multiple reasons, including high vaccine costs, low vaccine avail-
ability, logistic challenges in delivery, and potential interference
with water, sanitation, and hygiene control efforts. GAVI, the Vac-
cine Alliance, has invested US$114.5 million to expand the current
global OCV stockpile to 20 million doses by 2018 [8], with hopes to
curb the current cycle of low demand and low supply. The stock-
pile was created with a projected need of 2 million doses per year,
but shortages are already being anticipated. In the first year (2013)
of operation, half of this supply was used in emergency settings,
while the rest was used in preventive campaigns. With the main
supplier indicating limited production until 2018 [8], a need for
alternate sources of low cost OCV, as well as defining a process
to better allocate vaccine in a supply constrained environment is
paramount to ensure that the limited OCV is used in an fair manner.
The comparable safety and immunogenicity results demonstrated
for Euvichol to Shanchol in this trial is an important step in pursu-
ing WHO prequalification, which would make Euvichol the second
OCV suitable for use in lower income countries, where cholera still
has a significant economic and public health impact.
Conflict of interest
The authors declare no potential conflicts of interest.
Acknowledgements
This study was partly supported by a grant of technology
development, Gangwon Institute for Regional Program Evaluation,
Ministry of Trade, Industry and Administration.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.vaccine.2015.08.
075.
 Y.O. Baik et al. / Vaccine 33 (2015) 6360–6365
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