Typhoid Conjugate Vaccine Introduction in Navi Mumbai, India
Condition: Enteric Fever; Typhoid Fever; Salmonella Typhi Infection
MeSH terms: Typhoid Fever; Fever
Study type: Observational

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.
    

Intervention name(s): Typhoid Conjugate Vaccine
Intervention type(s): Biological
Intervention description(s): Typbar TCV Vi-TT (Vi capsular polysaccharide conjugated with tetanus toxoid protein) manufactured by Bharat Biotech International Limited
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.
      
Biospecimen description: 
      -  In the hospital surveillance component, blood cultures will be collected and tested for
           Salmonella Typhi and Paratyphi. Purified bacterial isolates of Salmonella Typhi and
           Paratyphi will be tested for antimicrobial resistance and stored for possible future
           genetic/genomic testing of the bacterial DNA.

        -  In a subset of the community surveillance component, dried blood spots will be collected
           onto filter paper and stored to test for antibodies against typhoid.