Safety and Immunogenicity of a Killed Oral Cholera Vaccine in Infants

Study Overview
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Brief Summary
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In order to assess whether the bivalent killed oral cholera vaccine may be used safely among infants who are most at risk for cholera, the investigators need to determine the safety and immunogenicity of the killed oral cholera vaccine among infants less than 1 year of age when given with the expanded program on immunization (EPI) vaccines including diptheria, pertussis and tetanus (DPT), oral polio vaccine (OPV), Hepatitis B vaccines and measles vaccine. Furthermore, the investigators also need to make sure that immune interference does not occur among all the other vaccine antigens given at the same time. Findings from this study will pave the way for the possible use of the killed whole cell oral cholera vaccine (OCV).

Detailed Description
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Cholera is an important public health problem worldwide, remaining endemic in most of the developing world at the same time causing outbreaks in areas where lapses in sanitation occur. A monovalent (anti-O1) oral killed cholera vaccine with a B-subunit was developed by Professor Jan Holmgren in Sweden and is now licensed to a pharmaceutical company in the United Kingdom. The technology for this vaccine was transferred to Vietnamese scientists at the National Institute of Hygiene and Epidemiology in Hanoi in the mid-1980s. The Vietnamese developed a bivalent vaccine, with killed 0139 cells and without the B-subunit. Since licensure, more than 9 million doses have been given without any report of serious adverse events. The vaccine has been reformulated in order to internationalize the vaccine. Phase II trials of this vaccine in Son La, Vietnam and Kolkata, India have found the vaccine to be safe with no serious adverse reactions associated with the vaccine. A phase III study of the reformulated vaccine is ongoing in Kolkata, India. The youngest person the vaccine has been administered to was a 1 year old. Previous studies with the B-subunit containing killed whole cell vaccine was found to be safe among infants as young as 6 months eliciting significant vibriocidal responses among 53% of vaccinees. However, no data is available regarding the use of the bivalent whole cell killed oral vaccine in infants. Due to the higher risk of cholera among infants, the possibility of introducing cholera vaccine as part of the expanded programme on immunization (EPI) needs to be investigated. Data regarding the safety and immunogenicity of the reformulated bivalent killed whole cell vaccine among infants needs to be gathered in order to pave the way for the possible use of this vaccine in cholera-endemic areas where infants and children are most at risk. Furthermore, there is no data regarding the concomitant use of this vaccine with other EPI vaccines given to young infants such as Diphtheria-Tetanus-whole cell Pertussis (DTwP), Oral Polio Vaccine (OPV) Hepatitis B and Measles vaccines. It would be important to determine if interference exists between the killed whole cell vaccine and other antigens included in the regular EPI schedule. Providing the killed whole cell vaccine in the context of the EPI will make it easier to introduce cholera vaccines in areas which are cholera-endemic.

Official Title
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Safety and Immunogenicity of a Killed Oral Cholera Vaccine Among Infants 10 Weeks to Less Than 12 Months of Age When Given Concomitantly With EPI Vaccines

Conditions
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Cholera, Diarrhea, Vibrio Infections

Intervention / Treatment
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* Biological: Bivalent killed oral cholera vaccine
* Biological: Killed Escherichia coli K12 placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria, Infants 10 weeks to 6 months of age at Day 0: Healthy infants aged from birth to 2 months who have not received OPV1, DTP1 or HepB2 will be recruited in Kolkata, North 24 Parganas, and South 24 Parganas All subjects must satisfy the following criteria at study entry: Male or female infants aged from birth to 2 months who the investigator believes will comply with the requirements of the protocol (i.e., available for follow-up visits and specimen collection) Written informed consent obtained from their parents/guardians Healthy subjects as determined by: Medical history Physical examination Clinical judgment of the investigator Inclusion Criteria, Infants 9 months to less than 12 months Healthy infants aged from 9 months to less than 12 months who have not received measles vaccine will be recruited in Kolkata, North 24 Parganas, and South 24 Parganas All subjects must satisfy the following criteria at study entry: Male or female infants aged from 9 months to less than 12 months who the investigator believes will comply with the requirements of the protocol (i.e., available for follow-up visits and specimen collection) Written informed consent obtained from their parents/guardians Healthy subjects as determined by: Medical history Physical examination Clinical judgment of the investigator Exclusion Criteria, Infants 10 weeks to 6 months of age at Day 0: Ongoing serious chronic disease Immunocompromising condition or therapy Diarrhea (having more frequent watery stools than usual within a 24 hour period) 6 weeks prior to enrollment Intake of any anti-diarrheal medicine in the past week Irritability, loss of appetite, general ill-feeling or vomiting in the past 24 hours Acute disease one week prior to enrollment, with or without fever. Temperature =>38C (oral) or axillary temperature =>37.5C warrants deferral of the vaccination pending recovery of the subject Receipt of antibiotics in past 14 days Receipt of killed oral cholera vaccine Receipt of live or killed enteric vaccine in 2 months Receipt of DTwP1, OPV1 or Hepatitis B2 vaccines One or two episodes of diarrhea lasting for more than 2 weeks in the past 2 months One or two episodes of abdominal pain lasting for more than 2 weeks in the past 2 months Z-score of < -2 on the weight for age WHO Child Growth Standards Exclusion Criteria, Infants 9 months to less than 12 months: Ongoing serious chronic disease Immunocompromising condition or therapy Diarrhea (3 or more loose/watery stools within a 24 hour period) 6 weeks prior to enrollment Intake of any anti-diarrheal medicine in the past week Abdominal pain/cramps, loss of appetite, general ill-feeling or vomiting in the past 24 hours Acute disease one week prior to enrollment, with or without fever. Temperature =>38C (oral) or axillary temperature =>37.5C warrants deferral of the vaccination pending recovery of the subject Receipt of antibiotics in past 14 days Receipt of killed oral cholera vaccine Receipt of live or killed enteric vaccine in last 4 weeks Receipt of measles-containing vaccine (MCV) One or two episodes of diarrhea lasting for more than 2 weeks in the past 6 months One or two episodes of abdominal pain lasting for more than 2 weeks in the past 6 months Disease episode potentially related to measles receipt of blood, blood products or a parenteral immunoglobulin preparation in past 3 months History of anaphylaxis, any serious vaccine reaction, allergy to eggs, egg products or to any measles vaccine component Any condition which in the opinion of the investigator might interfere with the evaluation of the study objectives Z-score of < -2 on the weight for age WHO Child Growth Standards

Ages Eligible for Study
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Minimum Age: 10 Weeks
Maximum Age: 11 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vaccine Group for Vibriocidal Assay<br>Killed whole cell cholera vaccine bled at day 42 for vibriocidal assay | Biological: Bivalent killed oral cholera vaccine<br>* Oral, 1.5 ml, given 2 times at least 14 days apart<br>* Other names: Shanchol;|
| Experimental: Vaccine Group for EPI Assay<br>Killed whole cell cholera vaccine bled at day 56 for EPI immunogenicity testing | Biological: Bivalent killed oral cholera vaccine<br>* Oral, 1.5 ml, given 2 times at least 14 days apart<br>* Other names: Shanchol;|
| Placebo Comparator: Placebo Group for Vibriocidal Assay<br>Placebo bled at day 42 for vibriocidal assay | Biological: Killed Escherichia coli K12 placebo<br>* oral, 1.5 ml per dose<br>|
| Placebo Comparator: Placebo Group for EPI Assay<br>Placebo bled at day 56 for EPI immunogenicity testing | Biological: Killed Escherichia coli K12 placebo<br>* oral, 1.5 ml per dose<br>|
| Experimental: Vaccine Group for Vibriocidal and Measles Assay<br>Killed whole cell cholera vaccine bled at day 14 and 28 for measles immunogenicity testing | Biological: Bivalent killed oral cholera vaccine<br>* Oral, 1.5 ml, given 2 times at least 14 days apart<br>* Other names: Shanchol;|
| Placebo Comparator: Placebo Group for Vibriocidal and Measles Assay<br>Placebo bled at day 14 and 28 for measles immunogenicity testing | Biological: Killed Escherichia coli K12 placebo<br>* oral, 1.5 ml per dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: proportion of subjects with diarrhea |  | entire study period | 
| Immunogenicity: proportion of subjects exhibiting 4-fold or greater rises in titers of serum vibriocidal antibodies, relative to baseline |  | 14 days after each dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric mean serum vibriocidal titers |  | 14 days after each dose | 
| Proportion of subjects with any of the following: a) immediate reactions 30 minutes and up to 3 days after each dose, b) serious adverse events occurring during the trial, c) any adverse event |  | entire study period | 
| Proportion of subjects with ≥ 0.1 mIU/ml of anti-diphtheria toxoid antibodies |  | 28 days after the third DPT dose | 
| Proportion of subjects with ≥ 0.1 mIU/ml of anti-tetanus toxoid antibodies |  | 28 days after the third DPT dose | 
| For initially seronegative subjects: proportion of subjects with ≥ 15 EU/ml of anti-pertussis IgG and for initially seropositive subjects, proportion with antibody titers equal to or greater than the initial titers prior to vaccination |  | 28 days after DPT dose | 
| Proportion of subjects with ≥ 10 mIU/ml of anti-HbS antibody |  | 28 days after the third dose of Hepatitis B vaccine | 
| Proportion of subjects with ≥ 8 fold dilution of anti-polio virus 1, 2, or 3 antibodies by micro-neutralization test |  | 28 days after the fourth dose of OPV | 
| Proportion of subjects with >150 mIU/ml measles IgG antibodies |  | 28 days after single dose of measles vaccine | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cholera, vaccine, Kolkata, West Bengal, India, immunogenicity, safety, infants, expanded programme on immunization