Safety and Immunogenicity of a Killed Oral Cholera Vaccine in Infants

• ClinicalTrials.gov Identifier: NCT00548054
• Recruitment Status: Unknown
• First Posted: October 23, 2007
• Last Update Posted: May 4, 2015
• Sponsor: International Vaccine Institute
• Collaborators: Indian Council of Medical Research; National Institute of Cholera and Enteric Diseases, India; Shantha Biotechnics Limited; Institute of Child Health
• Information provided by (Responsible Party): International Vaccine Institute

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Cholera; Diarrhea; Vibrio Infections	Biological: Bivalent killed oral cholera vaccine; Biological: Killed Escherichia coli K12 placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 300 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: 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
• Study Start Date: December 2015
• Estimated Primary Completion Date: August 2016
• Estimated Study Completion Date: December 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Safety: proportion of subjects with diarrhea [ Time Frame: entire study period ]
2. Immunogenicity: proportion of subjects exhibiting 4-fold or greater rises in titers of serum vibriocidal antibodies, relative to baseline [ Time Frame: 14 days after each dose ]

Secondary Outcome Measures :

1. Geometric mean serum vibriocidal titers [ Time Frame: 14 days after each dose ]
2. 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 [ Time Frame: entire study period ]
3. Proportion of subjects with ≥ 0.1 mIU/ml of anti-diphtheria toxoid antibodies [ Time Frame: 28 days after the third DPT dose ]
4. Proportion of subjects with ≥ 0.1 mIU/ml of anti-tetanus toxoid antibodies [ Time Frame: 28 days after the third DPT dose ]
5. 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 [ Time Frame: 28 days after DPT dose ]
6. Proportion of subjects with ≥ 10 mIU/ml of anti-HbS antibody [ Time Frame: 28 days after the third dose of Hepatitis B vaccine ]
7. Proportion of subjects with ≥ 8 fold dilution of anti-polio virus 1, 2, or 3 antibodies by micro-neutralization test [ Time Frame: 28 days after the fourth dose of OPV ]
8. Proportion of subjects with >150 mIU/ml measles IgG antibodies [ Time Frame: 28 days after single dose of measles vaccine ]

Eligibility Criteria

• Ages Eligible for Study: 10 Weeks to 11 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Contacts

Contact: Vijayalaxmi Mogasale, MD; 82-2-881-1151; vlmogasale@ivi.int

Contact: Binod Sah, MBBS, MS; 82-2-881-1149; bsah@ivi.int

Locations

India

National Institute of Cholera and Enteric Disease

Kolkata, West Bengal, India

Contact: Alok K Deb, PhD, MBBS 91-33-2363-3373 adeb2@yahoo.com

Principal Investigator: Alok K Deb, PhD, MBBS

Sponsors and Collaborators

International Vaccine Institute

Indian Council of Medical Research

National Institute of Cholera and Enteric Diseases, India

Shantha Biotechnics Limited

Institute of Child Health

Investigators

• Principal Investigator: Alok K Deb, PhD, MDDS; National Institute of Cholera and Enteric Disease

More Information

• Responsible Party: International Vaccine Institute
• ClinicalTrials.gov Identifier: NCT00548054
• Other Study ID Numbers: CH-WC-01
• First Posted: October 23, 2007
• Last Update Posted: May 4, 2015
• Last Verified: May 2015

Keywords provided by International Vaccine Institute:

cholera; vaccine; Kolkata; West Bengal; India; immunogenicity; safety; infants; expanded programme on immunization

Additional relevant MeSH terms:

Cholera; Vibrio Infections; Diarrhea; Signs and Symptoms, Digestive; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections