Safety and Immunogenicity of a Killed Oral Cholera Vaccine in Infants

International Vaccine Institute (IVI)

Status and phase: Unknown; Phase 2

Conditions: Diarrhea; Cholera; Vibrio Infections

Treatments: Biological: Killed Escherichia coli K12 placebo; Biological: Bivalent killed oral cholera vaccine

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT00548054

CH-WC-01

Details and patient eligibility

About

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).

Full 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.

Enrollment: 300 estimated patients

Sex: All

Ages: 10 weeks to 11 months old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

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

Exclusion Criteria, Infants 9 months to less than 12 months:

1. Ongoing serious chronic disease
2. Immunocompromising condition or therapy
3. Diarrhea (3 or more loose/watery stools within a 24 hour period) 6 weeks prior to enrollment
4. Intake of any anti-diarrheal medicine in the past week
5. Abdominal pain/cramps, 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 last 4 weeks
10. Receipt of measles-containing vaccine (MCV)
11. One or two episodes of diarrhea lasting for more than 2 weeks in the past 6 months
12. One or two episodes of abdominal pain lasting for more than 2 weeks in the past 6 months
13. Disease episode potentially related to measles
14. receipt of blood, blood products or a parenteral immunoglobulin preparation in past 3 months
15. History of anaphylaxis, any serious vaccine reaction, allergy to eggs, egg products or to any measles vaccine component
16. Any condition which in the opinion of the investigator might interfere with the evaluation of the study objectives
17. Z-score of < -2 on the weight for age WHO Child Growth Standards

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Single Group Assignment

Masking: Quadruple Blind

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300 participants in 6 patient groups, including a placebo group

Vaccine Group for Vibriocidal Assay

Experimental group

Description:

Killed whole cell cholera vaccine bled at day 42 for vibriocidal assay

Treatment:

Biological: Bivalent killed oral cholera vaccine

Vaccine Group for EPI Assay

Experimental group

Description:

Killed whole cell cholera vaccine bled at day 56 for EPI immunogenicity testing

Treatment:

Biological: Bivalent killed oral cholera vaccine

Placebo Group for Vibriocidal Assay

Placebo Comparator group

Description:

Placebo bled at day 42 for vibriocidal assay

Treatment:

Biological: Killed Escherichia coli K12 placebo

Placebo Group for EPI Assay

Placebo Comparator group

Description:

Placebo bled at day 56 for EPI immunogenicity testing

Treatment:

Biological: Killed Escherichia coli K12 placebo

Vaccine Group for Vibriocidal and Measles Assay

Experimental group

Description:

Killed whole cell cholera vaccine bled at day 14 and 28 for measles immunogenicity testing

Treatment:

Biological: Bivalent killed oral cholera vaccine

Placebo Group for Vibriocidal and Measles Assay

Placebo Comparator group

Description:

Placebo bled at day 14 and 28 for measles immunogenicity testing

Treatment:

Biological: Killed Escherichia coli K12 placebo