Safety, Immunogenicity and Compatibility With DTP of a Typhoid Fever Vaccine in Infants

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, immunogenicity, and compatibility of our Vi-rEPA conjugate administered to infants with their routine vaccinations. We propose to recruit 300 full term healthy newborns in Vietnam and randomly divide them to receive Vi-rEPA plus DTP, Hib-TT (not yet used in Vietnam) plus DTP, or DTP alone. Consent is obtained following interviews of mothers during prenatal visits, or after delivery. All vaccines will be administered at 2, 4, and 6 months. A booster of Vi-rEPA or Hib-TT conjugate will be administered at 12 months of age and reactions monitored at 6, 24 and 48 hours after each injection. Maternal and cord blood samples are collected during labor and at delivery. Blood will be taken at 7, and 12 months of age from all study infants and at 13 months from infants injected with Vi-rEPA or with Hib-TT at 12 months. The blood samples will be assayed for Vi, Hib, diphtheria, tetanus and pertussis antibodies. The levels of serum IgG anti-Vi elicited by Vi-rEPA administered to infants by the above schedule will be compared to those elicited by this vaccine in 2 to 5 year-olds in the efficacy trial conducted in Dong Thap Province, Vietnam.

Detailed Description
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Typhoid fever remains common, serious, and difficult-to-treat throughout the world including Vietnam. Limitations of the three licensed typhoid vaccines have prevented their use for routine vaccination of infants. The most recent, Vi polysaccharide typhoid vaccine is useful only in individuals greater than or equal to 5 years of age because of its age-related and T-cell independent properties. The immunogenicity of Vi in individuals less than 5 years-old has been improved by binding it to a protein. In 2 to 4-year-olds, 2 injections of the Vi conjugate induced higher levels of serum IgG anti-Vi than Vi in 5 to 14-year-olds. A double-blind, placebo controlled and randomized efficacy study in 2 -to-5 years old children in Vietnam showed an over-all efficacy after 27 months of active surveillance followed by 19 months of passive surveillance of 89%. Subsequently a dosage study in the same age group showed the highest antibody levels were induced by the 25 mcg dose. Now we wish to evaluate the safety, immunogenicity, and compatibility of our Vi-rEPA conjugate administered to infants with their routine vaccinations. We propose to recruit 300 full term healthy newborns in Vietnam and randomly divide them to receive Vi-rEPA plus DTP (Group A), Hib-TT (not yet used in Vietnam) plus DTP (Group B), or DTP alone (Group C). Maternal and cord blood are taken routinely on all deliveries in Vietnam; these sera will be retrieved for storage when consent is obtained following interviews of mothers during prenatal visits, or after delivery. All vaccines will be administered at 2, 4, and 6 months. A booster of Vi-rEPA or Hib-TT conjugate will be administered at 12 months of age and reactions monitored at 6, 24 and 48 hours after each injection. Blood will be taken at 7, and 12 months of age from all study infants and at 13 months from infants injected with Vi-rEPA or with Hib-TT at 12 months. The blood samples will be assayed for Vi, Hib, diphtheria, tetanus and pertussis antibodies. The levels of serum IgG anti-Vi elicited by Vi-rEPA administered to infants by the above schedule will be compared to those elicited by this vaccine in 2 to 5 year-olds in the efficacy trial conducted in Dong Thap.

Official Title
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Evaluation of the Safety, Immunogenicity and Compatibility With DTP of an Investigational Vi-rEPA Conjugate Vaccine for Typhoid Fever When Administered to Infants in Vietnam Concurrently With DTP

Conditions
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Typhoid Fever

Intervention / Treatment
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* Biological: Vi-rEPA conjugate vaccine for typhoid fever
* Biological: Hib-TT
* Biological: DTP


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Healthy full-term newborns. Birth weights of >=2500 grams. Exclusion criteria: Newborns without maternal and cord blood samples Newborns born to mothers with serious medical problems.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vi-rEPA plus DTP<br>Vi-rEPA and DTP at 2, 4, 6 months, and Vi-rEPA at 12 months | Biological: Vi-rEPA conjugate vaccine for typhoid fever<br>* Vi-rEPA contains a 25 ug/dose of Vi (Sanofi-Pasteur Lot 130) and rEPA in 0.2 N NaCl, 10 mM phosphate PH 7.2 and 0.01% thimerosal.<br>* Other names: Vi conjugate;Biological: DTP<br>* DTP, diphtheria, tetanus toxoid and pertussis vaccine were from the Ministry of Health, Vietnam for routine infant immunization<br>* Other names: EPI vaccine;|
| Active Comparator: Hib-TT plus DTP<br>Hib-TT and DTP at 2,4 and 6 months, Hib-TT at 12 months | Biological: Hib-TT<br>* Hib-TT is Hemophilus influenzae type b-tetanus toxoid conjugate vaccine (ActHib, NDC#49281-545-05 Sanofi-Pasteur, France) in single-dose vials containing 10 ugof Hib CP conjugated to 24 ug of tetanus toxoid<br>* Other names: Hib conjugate;Biological: DTP<br>* DTP, diphtheria, tetanus toxoid and pertussis vaccine were from the Ministry of Health, Vietnam for routine infant immunization<br>* Other names: EPI vaccine;|
| Active Comparator: EPI<br>DTP at 2,4 and 6 months | Biological: DTP<br>* DTP, diphtheria, tetanus toxoid and pertussis vaccine were from the Ministry of Health, Vietnam for routine infant immunization<br>* Other names: EPI vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Infants With Adverse Reactions After Vaccination | Number of infants with Fever>=38.0 C, Induration>=2.5cm at DTP site, Induration>=2.5cm,Vi-rEPA/Hib-TT site, Erythema>=2.5cm, at DTP site, Erythema>=2.5cm, Vi-rEPA/Hib-TT site, Inconsolable crying<4hr, Inconsolable crying>=4hr per injection with Vi conjugate vaccine given in conjunction with DTP in infants. | at 2, 4, 6 and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IgG Anti-Vi Levels | IgG anti-Vi was measured by ELISA and expressed as ELISA units (EU)in all sera. | cord sera, infants' sera at 7, 12 and 13 months | 
| Antibody Responses to Tetanus Toxoid, Diphtheria Toxoid, and Pertussis Toxin | IgG anti-diphtheria toxoid (DT), -tetanus toxoid (TT) and -pertussis toxin (PT) were measured by ELISA in sera of 30 randomly chosen infants per group. | Cord sera, and infants' sera at 7, 12 and 13 months of age | 
| Antibody Responses to Hib CP | IgG anti-Hib CP was measured by ELISA in sera of 30 randomly chosen infants per group | Cord sera and infant sera at 7, 12, and 13 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antibody, Reactions, Vaccine, Conjugate Vaccine, Typhoid Fever, Trial, Safety, Immunogenicity, Comparability, DTP