Infections with Salmonella enterica serovar Typhi (S. Typhi), S. Paratyphi A and S. Paratyphi B are responsible for the vast majority of enteric fevers globally and are a major public health concern. Additionally, Salmonella spp are category B pathogens that have the potential to be used as bio-terror weapons. The overall goal of this application is to advance the development of cross-protective vaccines against enteric fevers by identifying humoral and cell-mediated immune responses (CMI) which might play significant roles in protection. A secondary overall aim is to provide data to validate the S. Typhi /S. Paratyphi A bivalent vaccine approach to vaccination against enteric fevers. The proposed studies will take advantage of peripheral blood mononuclear cells and sera specimens obtained from subjects orally immunized with Ty21a and CVD 909 typhoid vaccines or with the attenuated CVD 1902 S. Paratyphi A candidate vaccine, from subjects challenged with wild-type (wt)-S. Typhi and wt-S. Paratyphi A and from typhoid and paratyphoid A patients in endemic areas. We will utilize the power of cutting edge immunologic platforms such as mass and conventional multichromatic flow cytometry analysis and sorting to characterize S. Typhi-, S. Paratyphi A-, and B-specific B([memory]) (BM), T [memory] ?, and T [regulatory] (T reg) responses, including their patterns of cytokine production and homing/chemokine receptor expression using a systems biology like approach. We will also perform immunoprofiling studies to identify genome-wide cross-reactive proteins that elicit serum antibody responses. Specifically, we propose to test the following hypotheses: (1) a defined set of CMI responses play a key role in cross-protection between S. Typhi and S. Paratyphi B infection in Ty21a-immunized subjects, (2) oral immunization of volunteers with an attenuated S. Paratyphi A vaccine strain (CVD 1902) or exposed to wt-S. Paratyphi A elicits a defined set of CMI responses against S. Paratyphi A antigens and infected cells that cross-react with S. Typhi and S. Paratyphi B antigens, and (3) oral immunization with the attenuated S. Paratyphi A CVD 1902 vaccine or exposure to wt-S. Paratyphi A (either in challenge studies or in endemic areas) elicits serum antibodies and BM, Beffector, and Breguiatory cells specific to S. Paratyphi A, as well as against Salmonella common antigens present in S. Typhi and S. Paratyphi B. These studies will contribute to the overall theme of this CETR application by providing novel and unique insights in humans that have the potential to advance the development of vaccine strategies to enteric fevers as well as other emerging enteric infections.

Public Health Relevance

In this proposal we will investigate whether immunization with attenuated S. Typhi or Salmonella Paratyphi A vaccines, or following natural exposure to wild-type organisms, elicit cross-protective multifunctional cell mediated and humoral responses to various Salmonella which cause enteric fevers, including S. Typhi and S. Paratyphi B. These studies have the potential to contribute much needed information to advance the development of broad-spectrum vaccines against enteric fevers.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
United States
Zip Code
Sheoran, Abhineet S; Pina-Mimbela, Ruby; Keleher, Alison et al. (2018) Infection with anthroponotic Cryptosporidium parvum does not fully protect the host against a subsequent challenge with C. hominis. Microbes Infect 20:267-270
Higginson, Ellen E; Ramachandran, Girish; Hazen, Tracy H et al. (2018) Improving Our Understanding of Salmonella enterica Serovar Paratyphi B through the Engineering and Testing of a Live Attenuated Vaccine Strain. mSphere 3:
Fuche, Fabien J; Sen, Sunil; Jones, Jennifer A et al. (2018) Characterization of Invasive Salmonella Serogroup C1 Infections in Mali. Am J Trop Med Hyg 98:589-594
Chen, Xinhua; Kelly, Ciaran P (2018) On and Off: A Dual Role for Cysteine Protease Autoprocessing of C difficile Toxin B on Cytotoxicity vs Proinflammatory Toxin Actions? Cell Mol Gastroenterol Hepatol 5:654-655
Zhang, Yongrong; Li, Shan; Yang, Zhiyong et al. (2018) Cysteine Protease-Mediated Autocleavage of Clostridium difficile Toxins Regulates Their Proinflammatory Activity. Cell Mol Gastroenterol Hepatol 5:611-625
Bolick, D T; Medeiros, P H Q S; Ledwaba, S E et al. (2018) The Critical Role of Zinc in a New Murine Model of Enterotoxigenic E. coli (ETEC) Diarrhea. Infect Immun :
Zhou, Fenfen; Hamza, Therwa; Fleur, Ashley S et al. (2018) Mice with Inflammatory Bowel Disease are Susceptible to Clostridium difficile Infection With Severe Disease Outcomes. Inflamm Bowel Dis 24:573-582
Sztein, Marcelo B (2018) Is a Human CD8 T-Cell Vaccine Possible, and if So, What Would It Take? CD8 T-Cell-Mediated Protective Immunity and Vaccination against Enteric Bacteria. Cold Spring Harb Perspect Biol 10:
Yu, Hua; Chen, Kevin; Sun, Ying et al. (2017) Cytokines Are Markers of the Clostridium difficile-Induced Inflammatory Response and Predict Disease Severity. Clin Vaccine Immunol 24:
Salerno-Gonçalves, Rosângela; Tettelin, Hervé; Lou, David et al. (2017) Use of a novel antigen expressing system to study the Salmonella enterica serovar Typhi protein recognition by T cells. PLoS Negl Trop Dis 11:e0005912

Showing the most recent 10 out of 58 publications