Mechanism Of Action
VAXCHORA contains live attenuated cholera bacteria that
replicate in the gastrointestinal tract of the recipient. Immune mechanisms
conferring protection against cholera following receipt of VAXCHORA have not
been determined. However, rises in serum vibriocidal antibody 10 days after
vaccination with VAXCHORA were associated with protection in a human challenge
study (Study 2) [See Immunogenicity].
Shedding of the vaccine strain was evaluated in the first
7 days post-vaccination in a study of 53 healthy adult vaccine recipients
(Study 3). VAXCHORA was shed in the stools of 11.3% [95% CI 4.3%, 23.0%] of
vaccine recipients on any day through 7 days post-vaccination. During the 7
days postvaccination, the proportion of subjects shedding was highest on day 7
(7.5% [95% CI 2.1%, 18.2%]). The duration of shedding of the vaccine strain is
Efficacy Against V. Cholerae Challenge
Study 2 was a randomized, double-blind, saline
placebo-controlled V. cholerae challenge study conducted in the US.
Subjects 18 through 45 years of age (N=197) with no prior history of cholera infection
or travel to a cholera-endemic area in the previous 5 years were randomized
according to a 1:1 ratio to receive one dose of VAXCHORA or placebo. In order
to identify the subset of subjects to be challenged, an unblinded statistician
prepared four randomly ordered lists of subjects per site, one list each for
vaccine recipients with blood type O, vaccine recipients with non-O blood
types, placebo recipients with blood type O, and placebo recipients with non-O
blood types. This was done to maintain a minimum of 60% blood group O subjects
in each treatment group. Individuals with type O blood are less likely to be
infected with V. cholerae, but are at risk for developing severe cholera
if infected. Each site was provided with a blinded version of the four lists
specific to its site and advised on the number of subjects from each list to
challenge. In the event that a subject was determined to be ineligible for
challenge, the site was instructed to select the next subject from the same
list as the ineligible subject
The challenges were split into 2 cohorts for 10 day and 3
month challenges. Subjects were admitted to an inpatient unit. Subjects had
nothing by mouth from midnight before ingestion of the challenge strain, except
for water, and had nothing by mouth for 90 minutes after ingestion of the
challenge strain. Approximately 1 minute prior to challenge, subjects ingested
120 mL sodium bicarbonate (NaHCO3) buffer. The oral challenge consisted of 1 x
105 CFU live wild type V. cholerae El Tor Inaba N16961 in 30
mL NaHCO3 buffer at 10 days or 3 months post-vaccination. The
co-primary objectives were to demonstrate the efficacy of a single dose of
VAXCHORA in the prevention of moderate to severe diarrhea following challenge
at 10 days and 3 months post-vaccination. Moderate to severe diarrhea was
defined as cumulative diarrheal purge ≥ 3 liters (L) within 10 days after
challenge. Diarrheal stool was defined as ≥ 2 unformed stools (takes
shape of container) collected during a 48 hour period ≥ 200 grams (g) or
a single unformed stool ≥ 300 g. Subjects were instructed to collect
every stool from the time of challenge until discharge from the inpatient unit.
Nursing staff or study personnel inspected all stool, graded the consistency of
the stool and calculated the total weight of diarrheal stool per day. Â Weight
of stool was converted to volume using the formula 1 g=1 mL. VAXCHORA
recipients challenged at 10 days post-vaccination and VAXCHORA recipients
challenged at 3 months postvaccination were compared with a pooled group of
placebo (saline) recipients challenged at 10 days or 3 months post-vaccination.
Of the 95 VAXCHORA recipients, 68 were challenged; 35
were challenged at 10 days postvaccination and 33 were challenged at 3 months
post-vaccination. Of the 102 placebo recipients, 66 were challenged; 33 were
challenged at 10 days post-vaccination and 33 at 3 months post- vaccination. Among
all randomized subjects, the mean age was 31.0 years. Overall, the mean age of
the challenge population was 31.4 years. More males were in the vaccine group
(71.6%) compared to the placebo group (54.9%). The majority of randomized
subjects were Black (67.5%), 29.4% were White, 0.5% were American
Indian/Alaskan Native, 0.5% were Asian, and 2.0% were other. There were 4.6% Hispanic
or Latino participants. Overall 50.3% had blood type O. Among subjects selected
for either challenge cohort, more males were challenged in the vaccine group
(76.5%) compared to the placebo group (57.6%). The majority (70.9%) of the challenge
population were Black, 25.4% were White, 0.7% were American Indian/Alaskan
Native, 0.7% were Asian, and 2.2% were other. There were 3.7% Hispanic or
Latino participants. Overall, 56.0% of challenged subjects had blood type O.
Vaccine efficacy against the occurrence of moderate to
severe diarrhea at 10 days post-vaccination was 90.3% [95% CI 62.7%, 100.0%]
and at 3 months post-vaccination was 79.5% [95% CI 49.9%, 100.0%] (Table 3).
Table 3: Vaccine Efficacy in the Prevention of
Moderate to Severe Diarrhea Following Challenge with V. cholerae O1 El
Tor Inaba at 10 Days and 3 Months Pos t-Vaccination (Intent-to-Treat Population)
||VAXCHORA 10 Day Challenge*‡
|VAXCHORA 3 Month Challenge*‡
|Combined Placebo*† 10 Day o r 3 Month Challenge‡
|Number of Subjects with Moderate or Severe Diarrhea (Attack Rate)¶
|Vaccine Efficacy %#Þ [95% CIβ]
|*Data are derived from Study 2 (NCT01895855).
†Combined placebo group comprised of all placebo recipients who were challenged
at either 10 days (N=33) or 3 months (N=33) following vaccination.
‡Challenge strain was V. cholerae O1 El Tor Inaba N16961.
§N=number of subjects challenged in each group.
¶Moderate or severe diarrhea (≥ 3 liters of diarrhea) within 10 days
#Vaccine Efficacy=[(Attack Rate in Placebo Group - Attack Rate in Vaccine
Group)/Attack Rate in Placebo Group] x 100.
ÞPre-specified criteria for success were that the lower bound of the two-sided
95% confidence interval for vaccine efficacy must be ≥30% in both the 10
Day and 3 Month challenge groups.
Vibriocidal Antibody Against The Vaccine Strain
A vibriocidal antibody assay was used to measure serum
levels of neutralizing antibodies against the vaccine strain.
Study 2 was a randomized, double-blind, saline
placebo-controlled V. cholerae challenge study conducted in adults 18
through 45 years of age. In the subset of subjects challenged in Study 2, 91% [95%
CI 82%, 97%] of vaccinees seroconverted prior to challenge and 9% developed
moderate to severe cholera following challenge, while 2% of placebo recipients
seroconverted prior to challenge and 59% developed moderate to severe cholera
following challenge. (Seroconversion was defined as a ≥ 4-fold rise in
serum vibriocidal antibody from baseline to 10 days post-vaccination.) Based on
the observed association between seroconversion and protection from V.
cholerae disease, seroconversion rate at 10 days post-vaccination was used
to evaluate response to vaccination in other age groups.
Study 1 was a randomized, double-blind, saline
placebo-controlled safety and immunogenicity study conducted in the US and
Australia. A total of 3146 subjects 18 through 45 years of age not previously exposed
to cholera were randomized 8:1 to receive one dose of VAXCHORA or placebo. The
mean age was 29.9 years; 45.2% were male; 68.3% were White, 25.6% were Black,
2.0% were Asian, 1.9% were multiracial, 1.4% were other, 0.4% were American
Indian/Alaskan Native, and 0.3% were Native Hawaiian/Pacific Islander. There
were 10.0% Hispanic or Latino participants.
In this study, the rates of seroconversion were 93.5%
[95% CI 92.5%, 94.4%] in vaccine recipients and 4% [95% CI 2%, 7%] in placebo
recipients at 10 days post-vaccination.
Study 4 was a randomized, double-blind,
placebo-controlled safety and immunogenicity study conducted in the US. A total
of 398 subjects 46 through 64 years of age with no prior history of cholera
infection or travel to a cholera-endemic area in the previous 5 years were
randomized 3:1 to receive one dose of VAXCHORA or placebo. Overall, the mean
age of the randomized population was 53.8 years; 45.7% were male; 74.9% were
White, 21.9% were Black, 1.8% were American Indian/Alaskan Native, 0.5% were
Asian, 0.5% were multiracial, 0.3% were Native Hawaiian/Pacific Islander, and
0.3% were other. There were 7.5% Hispanic or Latino participants.
Seroconversion rates at 10 days post-vaccination by
classical Inaba vibriocidal antibody among 46 through 64 year old subjects in
Study 4 were compared to those in 18 through 45 year old subjects in Study 1.
VAXCHORA recipients from Study 1 were in the same age group as those in Study
2, the V. cholerae challenge study.
Adults 46 through 64 years were shown to have a non-inferior
rate of seroconversion by classical Inaba vibriocidal antibody at 10 days
post-vaccination compared to adults 18 through 45 years of age (Table 4).
Table 4: Vibriocidal Antibody Seroconversion Against
Classical Inaba V. cholerae Vaccine Strain at 10 Days Post-Vaccination
in Adults 46 through 64 Years of Age (Study 4) Compared to Adults 18 through 45
Years of Age (Study 1) [Bridging Analysis Population]
||VAXCHORA Seroconversion % [95% CI‡]
|Study 4 (46 through 64 year olds)
||1 x 109
|Study 1 (18 through 45 year olds)
||1 x 109
|Difference in Seroconversion Rates§¶
|*Data are derived from Study 1 (NCT02094 586) and Study 4
†N=number of subjects with analyzable samples at Day 1 and Day 11.
§Seroconversion is defined as the percentages of subjects who had at least a 4 –fold
rise in vibriocidal antibody titer at 10 days post-vaccination compared to
¶Pre-specified non-inferiority criterion was that the lower bound of the
two-sided 95% confidence interval on the difference in seroconversion rate
(Study 4 minus Study 1) must be greater than -10 percentage points.
Vibriocidal Antibody Against Classical Ogawa, El Tor Inaba
And El Tor Ogawa
V. cholerae serogroup O1 consists of four major
subtypes: classical Inaba, classical Ogawa, El Tor Inaba and El Tor Ogawa.
Serum vibriocidal antibody against the three types of V. cholerae not
contained in the vaccine, namely classical Ogawa, El Tor Inaba and El Tor
Ogawa, was also measured in Study 2 and Study 4. The percentages of vaccine
recipients who seroconverted against each of the 4 major biotype/serotypes of V.
cholerae serogroup O1 at 10 days post- vaccination (71.4% to 91.4%) are shown
in Table 5.
Table 5: Seroconvers ion Rates 10 Days Pos
t-Vaccination for the Four Major V. cholerae O1 Serogroup Biotypes and
Serotypes in Studies 2 and 4 [Immunogenicity Evaluable Population]
||Study 2* (18 through 45 year olds) VAXCHORA
||Study 4* (46 through 64 year olds) VAXCHORA
||%‡ [95% CI§]
||% [95% CI]
|El Tor Inaba
|El Tor Ogawa
|*Data are derived from Study 2 (NCT01895855) and Study 4
†N=number of subjects with measurements at baseline and 10 days
post-vaccination. One subject in Study 2 did not have a Day 11 measurement and
was dropped from the analysis.
‡Seroconversion is defined as the percentages of subjects who had at least a 4
-fold rise in vibriocidal antibody titer at 10 days post-vaccination compared
to the titer measured at baseline.
¶VAXCHORA contains the classical Inaba strain of V. cholerae O1.