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    Pediatric Cell-Mediated Immune System and Response to Ty21a Typhoid Vaccination Compared to Adults

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    Author
    Rudolph, Mark Edward
    0000-0002-0942-0349
    Advisor
    Sztein, Marcelo B.
    Date
    2018
    Embargo until
    2019-07-01
    Type
    dissertation
    
    Metadata
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    Abstract
    Typhoid fever is a life-threatening disease caused by the human-restricted pathogen Salmonella enterica serovar Typhi (S. Typhi). The oral live-attenuated Ty21a typhoid vaccine protects against this severe disease by eliciting robust, multifunctional cell mediated immunity (CMI), shown to be associated with protection in wild-type S. Typhi challenge studies. Ty21a induces S. Typhi-responsive CD8+ and CD4+ T cells but little is known about the response to this vaccine in children. To address this important gap in knowledge, we have used mass cytometry to analyze pediatric and adult pre- and post-Ty21a vaccination T cells with both an HLA-E restricted and an autologous S. Typhi-antigen presentation model. Here, using conventional supervised analytical tools, we show adult T cells are more multifunctional at baseline than those obtained from children. Moreover, pediatric and adult T cells respond similarly to Ty21a vaccination, but adult responders remain more multifunctional. The use of the unsupervised dimensionality reduction tools allowed us to confirm these findings, as well as to identify increases and decreases in well-defined specific CD4+ and CD8+ T cell populations that were not possible to uncover using the conventional gating strategies. These findings evidenced age-associated maturation of multifunctional S. Typhi-responsive T cell populations, including those which have previously shown to be associated with protection from, and/or delayed onset of, typhoid disease. Further, in depth analysis of control stimulation conditions also found age-associated multifunctional T cell heterogeneity. These findings are likely to play an important role in improving pediatric vaccination strategies against S. Typhi and other enteric pathogens.
    Description
    2018
    Molecular Microbiology and Immunology
    University of Maryland, Baltimore
    Ph.D.
    Keyword
    Immunology
    mass cytometry
    pediatric immunology
    translational immunology
    Ty21a
    vaccine development
    Typhoid Fever
    Typhoid-Paratyphoid Vaccines
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/8990
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