# Defining immunological mechanisms of serovar cross-reactivity to develop broad spectrum protective vaccines for typhoidal and non-typhoidal Salmonella infections in humans

> **NIH NIH U19** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $719,928

## Abstract

ABSTRACT (CETR RP5, Sztein, PL)
 Infection with Salmonella spp. due to ingestion of contaminated food and water, including typhoidal
(caused largely by S. Typhi (ST) and S. Paratyphi A (PA)), as well as non-typhoidal (NTS) and invasive NTS
(iNTS) infections are major public health concerns in many areas of the World, including in the U.S. where NTS
causes 1.2 million illnesses annually. The rapid increase in multidrug resistance (MDR) and the lack of
vaccines against PA, NTS or iNTS have added a new sense of urgency for the development of vaccines
against these pathogens, and ideally broad-spectrum vaccines. One of the major obstacles in developing
vaccines against Salmonella spp. is that the precise immunological correlates of protection (CoP) against
either infection with wild-type (wt) organisms or vaccines remain unknown, in part because ST and PA are
human-restricted infections. The use of specimens from volunteers vaccinated and/or challenged with wt ST
has begun to uncover immunological T cell-mediated immunity (T-CMI) effector mechanisms which might be
associated with clinical outcome following challenge. No similar data is available for PA since the first wt PA
challenge has just been performed. A critical gap also remains in our understanding of the mechanisms of
antigen presentation for different Salmonella spp., which may underlie the development of effective adaptive T-
CMI and B cell responses, as well as the immune responses elicited in the gut microenvironment following
exposure to typhoidal and NTS infections.
 For these reasons, the overall goal of this application is to advance the development of vaccines against
PA as well as broad-spectrum vaccines against enteric fevers, iNTS, and NTS, by identifying protective cross-
reactive Salmonella spp. humoral, T effector, and regulatory immune responses, both systemically and in the
gut microenvironment, and by defining the mechanisms of antigen presentation against ST, PA, iNTS and NTS
that impact adaptive immune cell programming. To achieve these goals we will use PBMC from (i) a challenge
study with wt PA with known clinical outcomes (e.g., non-disease or disease), (ii) a study with attenuated PA
vaccine candidate strain CVD 1902 followed by challenge with wt PA, (iii) in vitro T cell priming systems and
(iv) three human intestinal models: (a) bioengineered 3-D organoids, (b) enteroids, and (c) explants to perform
the following Aims: Aim 1. Evaluate whether a defined set of B and T cellular responses in circulation are
associated with protection from bacteremic infection and/or bacteremia-negative clinical disease (e.g., fever)
following an oral challenge with wt PA in humans, and which regulatory mechanisms are involved in generating
these responses. Aim 2. Evaluate whether interactions between ST, PA, iNTS and NTS and dendritic cells
(DC) lead to the activation of diverse pathways which in turn determine the priming of defined T cell responses.
Aim 3. Contrast molecular biomarke...

## Key facts

- **NIH application ID:** 9893807
- **Project number:** 5U19AI142725-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Marcelo B. Sztein
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $719,928
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893807

## Citation

> US National Institutes of Health, RePORTER application 9893807, Defining immunological mechanisms of serovar cross-reactivity to develop broad spectrum protective vaccines for typhoidal and non-typhoidal Salmonella infections in humans (5U19AI142725-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9893807. Licensed CC0.

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