Clinical trial NCT03554213: Typhoid Conjugate Vaccine Introduction in Navi Mumbai, India
Official title: Evaluation of a Typhoid Conjugate Vaccine Introduction Program in Navi Mumbai, India
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Enteric Fever
Typhoid Fever
Salmonella Typhi Infection
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: Centers for Disease Control and Prevention
name: World Health Organization
name: National Institute of Cholera and Enteric Diseases, India
name: Bill and Melinda Gates Foundation
First posted: 2018-06-13
Enrollment: 17292
Sex: ALL
Minimum age (years): 6
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The focus of this study is children age 6 months to 16 years living in areas governed by Navi Mumbai Municipal Corporation (NMMC). The age range of children eligible to receive typhoid conjugate vaccine (TCV) in NMMC's TCV introduction program is 9 months to 15 years. For community surveys, only households with children \<16 years old will be selected.

The evaluation study will examine a slightly broader age range than NMMC's TCV vaccination program because TCV is licensed for \>6 month old children and because the vaccine introduction will occur over 1 year thus the oldest eligible children will be 16 years old at study end.

Brief summary: The purpose of this study is to evaluate the impact of a government-led typhoid conjugate vaccine introduction program on typhoid disease burden in Navi Mumbai, India.

Detailed description: A new generation of typhoid conjugate vaccines (TCVs) have been shown to be safe and provide long-lasting immunity in children. In India, Typbar TCV Vi-TT (Vi capsular polysaccharide conjugated with tetanus toxoid protein) is manufactured by Bharat Biotech International Limited (BBIL). Immunogenicity studies by BBIL showed \>90% detectable antibodies to Typbar TCV vaccine at 42 days and \>70% at 720 days in persons 2-45 years old. A single dose of vaccine was effective in children 6-23 months old with 98% seroconversion at 42 days and persistent high antibody titers at 720 days. Another randomized controlled trial study by University of Oxford tested Vi-TT with a human challenge model of typhoid fever in which participants ingested Salmonella Typhi after vaccination. Typhoid fever was diagnosed by clinical criteria and/or positive blood culture at 2 weeks in 77% of controls (n=31) as compared to 35% in the Vi-TT group (n=37) to give vaccine efficacy of 54% (95% confidence interval of 26-71). Typbar TCV has been licensed in India for children \>6 months old since 2013 and is currently used in the private sector. In January 2018, the World Health Organization (WHO) recommended the use of typhoid conjugate vaccines especially in those countries with the highest burden of disease and the highest burden of antimicrobial resistance. However, there are no field effectiveness studies yet for Typbar TCV.

In this study, a hybrid facility- and community-based typhoid surveillance strategy will be used to evaluate the impact of a government-led typhoid conjugate vaccine introduction program on typhoid disease burden in Navi Mumbai, India. Navi Mumbai is a metropolitan area extending from Mumbai with approximately 1.4 million people and wide demographic and socioeconomic strata, including slums. Navi Mumbai is comprised of 13 area nodes, and 8 of these nodes are under the jurisdiction of the local government body, Navi Mumbai Municipal Corporation (NMMC). Navi Mumbai has high enteric fever burden: a 2008 study found 98 blood culture-confirmed pediatric cases over 16 months in 2 hospitals with a majority of isolates exhibiting multi-drug resistance. Data from one private laboratory in 2015 showed over 225 S. Typhi cases including 3 cases with ceftriaxone resistance.

NMMC has decided to introduce TCV into public sector routine immunization services and will vaccinate all children 9 months to \<15 years old within its jurisdiction - estimated 390,000 children - with TCV over 2 years. NMMC government officials are collaborating with researchers from WHO India, Institute of Cholera and Enteric Diseases (NICED), Centers for Disease Control and Prevention (CDC), and Stanford University to implement the TCV introduction in a two-phase cluster-randomized program in order to allow rigorous evaluation of population impact. NMMC has 22 urban health posts (UHPs) that give routine childhood immunizations. UHPs were first grouped into 3 strata based on % of population living in slums: low, medium, or high. Half of the UHPs within each stratum were then randomly selected to receive TCV in 2018 (Phase 1) and the remaining UHPs to receive TCV one year later in 2019 (Phase 2).

Evaluation studies of NMMC's TCV introduction program include: impact on blood-culture confirmed typhoid fever; impact on clinical syndromes of febrile illness; vaccine safety; vaccine efficacy; vaccination campaign coverage and acceptability surveys; environmental water contamination with Salmonella Typhi; seroconversion associated with typhoid infection; and cost-effectiveness of typhoid conjugate vaccination campaign.

Eligibility criteria: Inclusion Criteria:

For overall study,

1. For hospital-based surveillance, children age 6 months to 16 years.
2. For community-based surveys, adult members of households with children \<16 years old.
3. Parental consent (and child assent for \>12 years) given.

For hospital-based surveillance for typhoid fever, additional criteria include: history of fever for \>72 hours within the last 7 days without upper respiratory tract symptoms and vesicular rash; strong clinical suspicion of enteric fever including ileal perforations; or diagnosis of enteric fever confirmed by positive blood cultures or histopathology. For outpatients, additional criterion of living in areas governed by Navi Mumbai Municipal Corporation.

For hospital-based surveillance of adverse events of special interest, timing will focus on one month prior to and 42 days after the vaccination campaign. Diagnoses included are: anaphylaxis, bronchospasm, urticaria, Guillain-Barré syndrome, meningitis, encephalitis, myelitis, seizures, thrombocytopenia, and sudden death.

For all community surveys, additional criterion of living in areas governed by Navi Mumbai Municipal Corporation.

Exclusion Criteria:

For all study components,

1. Already enrolled in same study component.
2. No informed consent or assent given.

For hospital-based surveillance for typhoid fever, additional exclusion criteria are: fever \<72 hours, symptoms of upper respiratory tract infection (coryza, rhinorrhea), and vesicular exanthem. For outpatients, those living outside of NMMC-governed areas will be excluded.

For community surveys, households without children \<16 years old and households in which there is no adult (\>18 years old) at time of survey will be excluded.

Primary outcomes:
measure: blood culture-confirmed typhoid fever
timeFrame: up to 24 months
Secondary outcomes:
measure: Adverse events following immunization
timeFrame: up to 4 months
measure: vaccination coverage
timeFrame: up to 18 months
measure: environmental water contamination with Salmonella Typhi
timeFrame: up to 24 months
measure: seroconversion associated with typhoid infection
timeFrame: up to 24 months
measure: cost-effectiveness of typhoid conjugate vaccination campaign
timeFrame: up to 24 months
measure: clinical syndromes of febrile illness
timeFrame: up to 18 months
Other outcomes:
Locations:
city: Navi Mumbai
country: India
facility: D. Y. Patil Medical College and Hospital, Nerul
city: Navi Mumbai
country: India
facility: Dr. Joshi's Central Clinical Microbiology Laboratory, Vashi
city: Navi Mumbai
country: India
facility: Dr. Yewale Multispecialty Hospital for Children, Vashi
city: Navi Mumbai
country: India
facility: Mahatma Gandhi Memorial (MGM) New Bombay Hospital, Vashi
city: Navi Mumbai
country: India
facility: Mathadi Hospital Trust, Koparkharaine
city: Navi Mumbai
country: India
facility: Navi Mumbai Municipal Corporation (NMMC) General Hospital, First Referral Unit (FRU), Vashi
Study officials:
affiliation: Stanford University
name: Stephen Luby, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centers for Disease Control and Prevention
name: Kashmira Date, MD MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institute of Cholera and Enteric Diseases (NICED)
name: Shanta Dutta, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: World Health Organization (WHO) - India
name: Pankaj Bhatnagar, MD
role: PRINCIPAL_INVESTIGATOR
References: