# Immune Mechanisms of Protection in S. Typhi Infection and Vaccination in Humans

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $567,403

## Abstract

Project Summary
 Limited understanding of the immunological mechanisms underlying protective immunity hampers the
development of novel vaccines, particularly against human-restricted enteric bacteria such as Salmonella Typhi.
The near exclusive reliance on circulating immune cells, which do not necessarily reflect the responses of
“resident” immune cells present in the gut, is another major limitation. Over the past 25 years, in studies largely
supported by this R01, and particularly during the last funding period (2013-2018), the PI reported major
advances in our understanding the B, T and innate immune responses elicited by the licensed Ty21a oral typhoid
and other candidate attenuated S. Typhi vaccines and, more recently, using specimens obtained from a wild
type (wt) S. Typhi human challenge model. The latter studies examined, among other key immune cell types,
the induction and activation of memory T (TM) subsets and regulatory T cells (TREG), demonstrating, for the first
time, an association between defined multifunctional CD8+ subsets and regulatory T cell (TREG) responses and
clinical outcome upon challenge. However, many key questions regarding whether the same T subsets are
elicited following Ty21a immunization and are associated with protection from challenge with wt S. Typhi and
the induction and persistence of gut and systemic immunity following vaccination remain unexplored. These
major gaps should be addressed before we can apply this knowledge to the development of more effective oral
vaccines. To directly address these major gaps, we propose to continue and greatly expand our findings during
the current funding period by evaluating the hypotheses that the characteristics of CD4 and CD8 T-CMI S. Typhi-
specific responses, including TM subsets (e.g., TM, T effector (TEFF), T stem-cell like memory (TSCM), and TREG at
baseline and at the early stages after immunization and/or challenge with wt S. Typhi play critical roles in
protection from infection and persistence of immunity in humans. To this end we will use unique specimens from
adults vaccinated and/or challenged with wt S. Typhi, and gut biopsies from participants vaccinated with Ty21a
to: Aim 1. Evaluate the hypothesis that defined T cell subsets with gut-homing potential present at baseline and
those elicited during the early stages following Ty21a vaccination and/or wt S. Typhi challenge are associated
with robust immunity, protection from clinical disease and persistent immunity. Aim 2. Evaluate the hypothesis
that protection from infection following wt S. Typhi challenge and robust effector and memory immunity following
vaccination is associated with defined regulatory T cell (TREG) responses and depends on a balanced TEFF / TM /
TSCM / and TREG responses at baseline and after immunization. Aim 3. Evaluate the hypothesis that robust
terminal ileum (TI) CD4 and CD8 TEFF, TM, and T resident/memory (TRM) responses in the absence of TREG cells
is associated with long-term mai...

## Key facts

- **NIH application ID:** 9952293
- **Project number:** 5R01AI036525-21
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Marcelo B. Sztein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $567,403
- **Award type:** 5
- **Project period:** 1994-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952293

## Citation

> US National Institutes of Health, RePORTER application 9952293, Immune Mechanisms of Protection in S. Typhi Infection and Vaccination in Humans (5R01AI036525-21). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9952293. Licensed CC0.

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