T Cell Responses to Salmonella Typhi Immunization in humans: Age matters.

Salmonella Typhi is the cause of typhoid fever. Typhoid fever is a systemic infection that is an important source of illness and death in low-resource areas and remains a major problem worldwide.

To combat and contain S. Typhi, it is necessary to implement effective prevention and treatment strategies to control both acutely and chronically infected individuals. Studies have shown that robust, multifunctional baseline CD8⁺ T cell responses to S. Typhi antigen presentation are associated with protection from, and/or delayed onset of typhoid disease (Fresnay et al., J. Translational Medicine 14: 62, 2016). Therefore, a successful attenuated typhoid vaccine should aim to induce these cell-mediated immunological (T-CMI) responses. Previous studies have shown that the oral live-attenuated Ty21a vaccination induce T-CMI in approximately two-thirds of adult recipients. Because typhoid fever is a disease that disproportionally impacts children in the developing world, successful vaccination strategies require protecting pediatric populations in endemic regions.

Unfortunately, very limited information is available that addresses potential differences between pediatric and adult T cell responses to vaccination, especially regarding oral, live-attenuated vaccines. In general peripheral naïve T cell populations are higher in younger children, with memory T cell phenotypes increasing throughout life. Scientists from the Center for Vaccine Development and Global Healthy at the University of Maryland, Baltimore led by Professor Marcelo Sztein, have previously shown that following mitogenic stimulation, CD8⁺ T cell activation—as defined by CD69 expression—increases throughout adolescence, plateauing by the age of 15-years-old. Further, they identified significantly lower mitogen-induced CD8⁺ T effector/memory (T_EM) multifunctional effector responses in younger children compared to adults (Rudolph, et. al., Frontiers in Immunology 20, March 2018).

HLA-E is a highly conserved non-classical class I MHC, capable of presenting the MHC leader peptide to CD94/NKG2 as a means of regulating natural killer cell function. In addition to this innate, inhibitory presentation of self-antigens, HLA-E can present a limited repertoire of peptides from a variety of viral and bacterial pathogens to CD8⁺ T cells, leading to activation of adaptive immune responses separate from those that require classical HLA restriction.

In a new follow up research by Professor Marcelo Sztein and his colleagues, the research group used an established S. Typhi infected HLA-E-restricted antigen presentation model to explore the variability of CD8⁺ T cell responses among pediatric and adult Ty21a vaccine recipients. The new work has been recently published in the journal Frontiers in Immunology.

The authors observed that the proportions of T cells in circulation showed no changes following vaccination among 6-15-year-old children, 16-17-year-old children, or adult (20-65-year-old) participants and reaffirmed previous reporting that the percentage of CD8⁺ T_EM are lower in children than in adults. They also identified significant age- and sex-associated differences among the CD8⁺ T_EM among pediatric males (ages 6-17) and females (ages 11-17) compared with adult males (ages 36-65) regardless of vaccination status.

Furthermore, they found that unstimulated adult PBMC pre-vaccination showed significantly higher CD69 expression than 6-15 years old pediatric participants with a trend toward significance in the post-Ty21a time point. Finally, cells were pooled into a cluster analysis algorithm, and then parsed into age groups (6-15, 16-17and 20-65 years old), from which it was noted that the younger pediatric participants clearly showed fewer cells in multifunctional clusters containing protection-associated phenotypes compared to the older pediatric and adult participants at both pre- and post- vaccine time points. Finally, the study provides compelling evidence that post-Ty21a S. Typhi-antigen-responsive HLA-E-restricted CD8⁺ T_EMRA show the greatest differences between age groups, with adults and older pediatric recipients exhibiting higher percentages of multi-functional cells as observed by both conventional gating and tSNE analysis.

This study, out of the Center for Vaccine Development and Global Health at the University of Maryland, Baltimore suggests one possible mechanism behind previously reported lower efficacy among children vaccinated with Ty21a. The study could prove of great importance in the development of new, more effective oral live attenuated vaccines for use in pediatric populations.