Investigation of Innate Immune Responses to Salmonella Typhi in Typhoid Fever in Children and Adults Patients and Vaccinees in Dhaka, Bangladesh

Description of the Research Project: It has been previously shown that IFN-gamma and IL-17 are increased in typhoid fever patients. It was shown that S. Typhi infection induces antibody responses against a number of key typhoid antigens (LPS) HlyE, Flagellar protein FliC and chaperon protein EcpD). In the enteric diarrheal disease cholera, MAIT cells are activated and associated LPS specific antibody responses are generated. In a human challenge model study, it has been shown that CD8+ T cell memory cells are key correlates of protection against typhoid fever. The live attenuated typhoid vaccine (TY21a) also induces MAIT cells after immunization. It has been shown that IL-12, IL-15, IL-18 induce memory-like NK cells in a mouse model and IL-21 induces memory-like NK cells protective against Mycobacterium tuberculosis infection. The role of activated MAIT cells, and cytokine induced memory-like NK cells in typhoid fever currently unknown.

One of the multiple killing mechanism employed by neutrophil is the release of neutrophil extracellular traps (NETs) that contain myeloperoxidase (MPO), elastase, lysozyme and defensins. Infection induces releases of NETs to trap microbial pathogens. Neutrophils isolated from typhoid fever patients release NETs in and that neutrophil NET release is primed by vaccination with a subunit-conjugate vaccine.

Study intervention: Typbar-TCV is a Typhoid Vi capsular polysaccharide tetanus toxoid conjugate vaccine. Typbar-TCV is the world's 1st clinically proven conjugate typhoid vaccine. This vaccine is WHO pre-qualified and approved for children and infants less that 2 years of age. During the Phase III clinical study, a single dose of Typbar-TCV elicited 4-fold seroconversion rates of 98.05%, 99.17% and 92.13% in subjects between greater than 6 months to 2 years, >2 to 15 years and >15 to 45 years respectively. Each volunteer in the vaccination arm of the study will receive 25 ug of Typbar-TCV vaccine administered as 0.5 ml single intracellular dose.

Storage condition: The vaccine will be stored at +2-8C and cold chain will be maintained at all times.

Study participants and sample collection: The investigators will collect 8-10 ml of blood from adults and 3-5 ml of blood from children who will be suspected typhoid fever patients (age 1-59 years) at enrollment (day1) and if patient is S. Typhi/Paratyphi culture confirmed then two more blood samples (2-5 days and 27-33 days later) will be collected. The investigators will collect 8-10 ml of blood from adults and 3-5 ml of blood from children before vaccination (day 0) and two more blood samples after one dose of vaccination at day 7 (6-8 days later) [13] and at day 30 (27-33 days later). Peripheral blood mononuclear cells (PBMCs) and neutrophils will be isolated from blood samples and will be used for different assays (Polymorphprep kit). Plasma samples will be separated to measure antibody response to infection and vaccination.