Cholera, Diarrhea, Vibrio Infections
Conditions
Keywords
cholera, vaccine, Kolkata, West Bengal, India, immunogenicity, safety, infants, expanded programme on immunization
Brief summary
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
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.
Interventions
BIOLOGICALBivalent killed oral cholera vaccine
Oral, 1.5 ml, given 2 times at least 14 days apart
BIOLOGICALKilled Escherichia coli K12 placebo
oral, 1.5 ml per dose
Sponsors
Indian Council of Medical Research
National Institute of Cholera and Enteric Diseases, India
Shantha Biotechnics Limited
Institute of Child Health
International Vaccine Institute
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
10 Weeks to 11 Months
Healthy volunteers
Yes
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: 1. 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) 2. Written informed consent obtained from their parents/guardians 3. 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: 1. 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) 2. Written informed consent obtained from their parents/guardians 3. 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: 1. Ongoing serious chronic disease 2. Immunocompromising condition or therapy 3. Diarrhea (having more frequent watery stools than usual within a 24 hour period) 6 weeks prior to enrollment 4. Intake of any anti-diarrheal medicine in the past week 5. Irritability, loss of appetite, general ill-feeling or vomiting in the past 24 hours 6. 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 7. Receipt of antibiotics in past 14 days 8. Receipt of killed oral cholera vaccine 9. Receipt of live or killed enteric vaccine in 2 months 10. Receipt of DTwP1, OPV1 or Hepatitis B2 vaccines 11. One or two episodes of diarrhea lasting for more than 2 weeks in the past 2 months 12. One or two episodes of abdominal pain lasting for more than 2 weeks in the past 2 months 13. Z-score of \< -2 on the weight for age WHO Child Growth Standards
Design outcomes
Primary
| Measure | 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
| Measure | Time frame |
|---|---|
| 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 |
| Geometric mean serum vibriocidal titers | 14 days after each dose |
| Proportion of subjects with ≥ 0.1 mIU/ml of anti-tetanus toxoid antibodies | 28 days after the third DPT dose |
| Proportion of subjects with ≥ 0.1 mIU/ml of anti-diphtheria toxoid antibodies | 28 days after the third DPT dose |
| Proportion of subjects with >150 mIU/ml measles IgG antibodies | 28 days after single dose of measles vaccine |
| 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 |
| 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 |
Countries
India
Contacts
Primary ContactVijayalaxmi Mogasale, MD
Backup ContactBinod Sah, MBBS, MS
Outcome results
None listed