Effect of Extended Dose Intervals on the Immune Response to Oral Cholera Vaccine

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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