Brief Title
Effect of Extended Dose Intervals on the Immune Response to Oral Cholera Vaccine
Official Title
Effect of Extended Dose Intervals on the Immune Response to Oral Cholera Vaccine
Brief Summary
Cholera is a life-threatening disease if prompt actions are not taken. The most recent
estimates of the global burden of cholera estimate that there are more than 1.3 billion
people at risk. Of which, 2.86 million (range: 1.3-4.0 million) will contract cholera and
95,000 (21,000-143,000) will die each year. A safe, effective, and affordable killed
whole-cell oral cholera vaccine (OCV) is now being used widely to prevent cholera in areas at
risk. This regimen demonstrated 65% efficacy retained for at least 3 years and even up to 5
years in an endemic setting.
The primary aim of this project is to determine changes in the vibriocidal geometric mean
titers (GMT) in subjects who receive the second dose of oral cholera vaccine (OCV) at
different intervals: 2 weeks, or 6 months following the first dose of vaccine. Secondary aims
include a) vibriocidal antibody response rates in subjects who receive OCV at 2 weeks or 6
months following the first dose of vaccine, b) age specific serum vibriocidal GMTs following
the second dose among participants given the second dose of OCV at intervals of 2 weeks or 6
months following the first dose of vaccine, c) GMT and antibody response rates of
Immunoglobulin A (IgA) and Immunoglobulin G (IgG) anti-lipopolysaccharide (anti-LPS) as
measured by ELISA following the second dose among participants given the second dose of OCV
at intervals of 2 weeks or 6 months following the first dose of vaccine. Our hypothesis is
that the vibriocidal GMT following the second dose, when given after 6 months will not be
inferior to the response when the second dose is given according to the standard interval of
two weeks.
Detailed Description
Cholera is a life-threatening disease if prompt actions are not taken. The most recent
estimates of the global burden of cholera estimate that there are more than 1.3 billion
people at risk. Of which, 2.86 million (range: 1.3-4.0 million) will contract cholera and
95,000 (21,000-143,000) will die each year. A safe, effective, and affordable killed
whole-cell oral cholera vaccine (OCV) is now being used widely to prevent cholera in areas at
risk. This regimen demonstrated 65% efficacy retained for at least 3 years and even up to 5
years in an endemic setting.
As described in the package insert, the standard dosing schedule of the OCV is two doses with
the second dose given 2 weeks after the first. In several campaigns, it was felt to
appropriate to give a single dose to twice as many people and to give the second dose at a
later time when this was logistically possible. In fact, modelling of the impact of OCV
during an outbreak finds that when the vaccine supply is limited (as it is currently), more
cases are prevented if a single dose strategy is used since a single dose can be provided to
twice as many people. Even if the efficacy is a bit lower, the number of cases prevented will
be higher. Even the individual person in this situation will be better off if more of his
neighbors also receive vaccine since he benefits from the herd protection when more people
are vaccinated.
A single dose strategy was used during an outbreak in Zambia in 2015-16, but this first dose
was then followed up with a second dose after 6 to 8 months. I was also used in Haiti in
2016-17 following the hurricane. While the delayed second dose strategy has been used and
will likely continue to be used during outbreaks or during humanitarian crises, there is no
feasible way to assess the relative effectiveness against clinical cholera comparing a
two-week interval with a delayed second dose strategy.
While clinical effectiveness trials are not feasible, serological responses comparing
different dose intervals are possible. One such study found that vibriocidal titers were
similar if the second dose was given either 2 week or 4 weeks after the first , but studies
have not been done with longer dose intervals, as was used in Zambia and Haiti.
The proposed study will determine if giving the second dose of the OCV using a longer
interval will result in a response to the second dose that is not inferior, or perhaps even
results in a more prolonged elevated vibriocidal titre. From an immunological standpoint,
there could be advantages to a longer dose interval if this resulted in a true booster
response which sustained high titre of antibody. While acknowledging that the vibriocidal
titer is not an established correlate of protection, it is the best correlate of the immune
response following vaccination. It seems logical that a sustained high titer is likely to be
more effective. Unfortunately, the clinical trials comparing the 2 week and 4 week interval
with Shanchol only examined the serum titers shortly after the dosing (about 2 weeks).
Follow-up serum samples were not obtained to discern how these dose intervals compared in
terms of duration of elevated serum titres.
Recent studies have found that children <5 years of age are less well protected than older
individuals even though their serum antibody response rates (take rates) were similar to the
older subjects when the serum was collected about two weeks after the vaccine doses were
administered. These immunogenicity studies have not, however, examined antibody titers when
blood samples were obtained after a longer time interval. Therefore, it is not known if the
antibody titers decline at the same rate as older subjects. It could be that GMT titers are
lower or that titers fall more rapidly in the young children, and a different dosing interval
could maintain higher titres. To compare antibody responses in different age groups, we plan
to stratify groups into age 1-4, 5-14, and 15 years and older.
Study Phase
Phase 4
Study Type
Interventional
Primary Outcome
Change in Vibriocidal GMT
Secondary Outcome
Vibriocidal Antibody Response Rates
Condition
Cholera
Intervention
Oral Cholera Vaccine
Study Arms / Comparison Groups
Shanchol Dose-interval Group 1
Description: Participants in Dose-Interval Group 1 (DIG-1) will receive the oral cholera vaccine, Shanchol, according to the manufacturer instructions: in 2 doses at Day 0 and two weeks later (Day 14).
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Biological
Estimated Enrollment
120
Start Date
November 16, 2017
Completion Date
December 1, 2020
Primary Completion Date
October 16, 2019
Eligibility Criteria
Inclusion Criteria:
1. Age ≥1 year, stratified into different age groups
2. Living in the Waya Clinic Catchment Area
3. Good health condition, without clinically significant medical history (by participant
or guardian, in case of minor)
4. Not pregnant for female subjects.
5. Available to participate for the study duration, including all planned follow-up
visits for up to 9 months from screening.
6. Signed informed consent
Exclusion Criteria:
1. Presence of a significant medical or psychiatric condition (Examples include:
Diagnosis and treatment of tuberculosis (TB) or HIV; renal insufficiency; hepatic
disease; oral or parenteral medication known to affect the immune function, such as
corticosteroids, other immunosuppressant drugs; or behavioural or memory issues)
2. Ever having received oral cholera vaccine.
3. Receipt of an investigational product (within 30 days before vaccination).
4. History of diarrhoea in 7 days prior to first dose of vaccine (defined as ≥3 unformed
loose stools in 24 hours).
5. History of chronic diarrhea (lasting for more than 2 weeks in the past 6 months)
6. Current use of laxatives, antacids, or other agents to lower stomach acidity?
7. Planning to become pregnant in the next 2 years.
Gender
All
Ages
1 Year - N/A
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Contacts
Amanda K Debes, PhD, ,
Location Countries
Zambia
Location Countries
Zambia
Administrative Informations
NCT ID
NCT03373669
Organization ID
IRB00008066
Responsible Party
Sponsor
Study Sponsor
Johns Hopkins Bloomberg School of Public Health
Study Sponsor
Amanda K Debes, PhD, Principal Investigator, Johns Hopkins Bloomberg School of Public Health
Verification Date
April 2021