Safety, Immunogenicity and Compatibility With DTP of a Typhoid Fever Vaccine in Infants - Full Text View

Purpose

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.

Condition	Intervention	Phase
Typhoid Fever	Biological: Vi-rEPA conjugate vaccine for typhoid fever Biological: Hib-TT Biological: DTP	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Prevention
Official Title:	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

Resource links provided by NLM:

MedlinePlus related topics: Diphtheria Fever Haemophilus Infections Tetanus Whooping Cough

U.S. FDA Resources

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

Number of Infants With Adverse Reactions After Vaccination [ Time Frame: at 2, 4, 6 and 12 months ] [ Designated as safety issue: Yes ]
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.

Secondary Outcome Measures:

IgG Anti-Vi Levels [ Time Frame: cord sera, infants' sera at 7, 12 and 13 months ] [ Designated as safety issue: No ]
IgG anti-Vi was measured by ELISA and expressed as ELISA units (EU)in all sera.
Antibody Responses to Tetanus Toxoid, Diphtheria Toxoid, and Pertussis Toxin [ Time Frame: Cord sera, and infants' sera at 7, 12 and 13 months of age ] [ Designated as safety issue: No ]
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.
Antibody Responses to Hib CP [ Time Frame: Cord sera and infant sera at 7, 12, and 13 months ] [ Designated as safety issue: No ]
IgG anti-Hib CP was measured by ELISA in sera of 30 randomly chosen infants per group

Enrollment:	301
Study Start Date:	July 2006
Study Completion Date:	January 2011
Primary Completion Date:	April 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Vi-rEPA plus DTP Vi-rEPA and DTP at 2, 4, 6 months, and Vi-rEPA at 12 months	Biological: Vi-rEPA conjugate vaccine for typhoid fever 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. Other Name: Vi conjugate Biological: DTP DTP, diphtheria, tetanus toxoid and pertussis vaccine were from the Ministry of Health, Vietnam for routine infant immunization Other Name: EPI vaccine
Active Comparator: Hib-TT plus DTP Hib-TT and DTP at 2,4 and 6 months, Hib-TT at 12 months	Biological: Hib-TT 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 Other Name: Hib conjugate Biological: DTP DTP, diphtheria, tetanus toxoid and pertussis vaccine were from the Ministry of Health, Vietnam for routine infant immunization Other Name: EPI vaccine
Active Comparator: EPI DTP at 2,4 and 6 months	Biological: DTP DTP, diphtheria, tetanus toxoid and pertussis vaccine were from the Ministry of Health, Vietnam for routine infant immunization Other Name: EPI vaccine

Detailed Description:

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.

Eligibility

Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00342628

Locations

Vietnam
Thanh Thuy District Health Center
Viet Tri, Phu Tho Province, Vietnam

Sponsors and Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

Study Director:

Feng-Ying (Kimi) Lin, MD, MPH

PDMI, NICHD, NIH

More Information

Publications:

Acharya IL, Lowe CU, Thapa R, Gurubacharya VL, Shrestha MB, Cadoz M, Schulz D, Armand J, Bryla DA, Trollfors B, et al. Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi. A preliminary report. N Engl J Med. 1987 Oct 29;317(18):1101-4.

Crump JA, Mintz ED. Global trends in typhoid and paratyphoid Fever. Clin Infect Dis. 2010 Jan 15;50(2):241-6. Review.

Gilman RH, Terminel M, Levine MM, Hernandez-Mendoza P, Hornick RB. Relative efficacy of blood, urine, rectal swab, bone-marrow, and rose-spot cultures for recovery of Salmonella typhi in typhoid fever. Lancet. 1975 May 31;1(7918):1211-3.

Klugman KP, Gilbertson IT, Koornhof HJ, Robbins JB, Schneerson R, Schulz D, Cadoz M, Armand J. Protective activity of Vi capsular polysaccharide vaccine against typhoid fever. Lancet. 1987 Nov 21;2(8569):1165-9.

Kossaczka Z, Lin FY, Ho VA, Thuy NT, Van Bay P, Thanh TC, Khiem HB, Trach DD, Karpas A, Hunt S, Bryla DA, Schneerson R, Robbins JB, Szu SC. Safety and immunogenicity of Vi conjugate vaccines for typhoid fever in adults, teenagers, and 2- to 4-year-old children in Vietnam. Infect Immun. 1999 Nov;67(11):5806-10.

Mai NL, Phan VB, Vo AH, Tran CT, Lin FY, Bryla DA, Chu C, Schiloach J, Robbins JB, Schneerson R, Szu SC. Persistent efficacy of Vi conjugate vaccine against typhoid fever in young children. N Engl J Med. 2003 Oct 2;349(14):1390-1. PubMed PMID: 14523155.

Levine MM, Ferreccio C, Abrego P, Martin OS, Ortiz E, Cryz S. Duration of efficacy of Ty21a, attenuated Salmonella typhi live oral vaccine. Vaccine. 1999 Oct 1;17 Suppl 2:S22-7.

Lin FY, Vo AH, Phan VB, Nguyen TT, Bryla D, Tran CT, Ha BK, Dang DT, Robbins JB. The epidemiology of typhoid fever in the Dong Thap Province, Mekong Delta region of Vietnam. Am J Trop Med Hyg. 2000 May;62(5):644-8.

Lin FY, Ho VA, Khiem HB, Trach DD, Bay PV, Thanh TC, Kossaczka Z, Bryla DA, Shiloach J, Robbins JB, Schneerson R, Szu SC. The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five-year-old children. N Engl J Med. 2001 Apr 26;344(17):1263-9.

Ochiai RL, Acosta CJ, Danovaro-Holliday MC, Baiqing D, Bhattacharya SK, Agtini MD, Bhutta ZA, Canh do G, Ali M, Shin S, Wain J, Page AL, Albert MJ, Farrar J, Abu-Elyazeed R, Pang T, Galindo CM, von Seidlein L, Clemens JD; Domi Typhoid Study Group. A study of typhoid fever in five Asian countries: disease burden and implications for controls. Bull World Health Organ. 2008 Apr;86(4):260-8. PubMed PMID: 18438514; PubMed Central PMCID: PMC2647431.

Sinha A, Sazawal S, Kumar R, Sood S, Reddaiah VP, Singh B, Rao M, Naficy A, Clemens JD, Bhan MK. Typhoid fever in children aged less than 5 years. Lancet. 1999 Aug 28;354(9180):734-7.

Szu SC, Stone AL, Robbins JD, Schneerson R, Robbins JB. Vi capsular polysaccharide-protein conjugates for prevention of typhoid fever. Preparation, characterization, and immunogenicity in laboratory animals. J Exp Med. 1987 Nov 1;166(5):1510-24.

Taylor DN, Levine MM, Kuppens L, Ivanoff B. Why are typhoid vaccines not recommended for epidemic typhoid fever? J Infect Dis. 1999 Dec;180(6):2089-90.

Responsible Party:	National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )
ClinicalTrials.gov Identifier:	NCT00342628 History of Changes
Other Study ID Numbers:	999999050, OH99-CH-N050
Study First Received:	June 19, 2006
Results First Received:	March 30, 2012
Last Updated:	May 22, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):

Antibody
Reactions
Vaccine
Conjugate Vaccine
Typhoid Fever

Trial
Safety
Immunogenicity
Comparability
DTP

Additional relevant MeSH terms:

Fever
Typhoid Fever
Body Temperature Changes
Signs and Symptoms

Salmonella Infections
Enterobacteriaceae Infections
Gram-Negative Bacterial Infections
Bacterial Infections

ClinicalTrials.gov processed this record on June 18, 2013