Non-typhoidal Salmonella (NTS) are increasingly being recognized as important causes of invasive disease (e.g. sepsis, meningitis) in the very young and the elderly in the USA. The growing resistance of NTS strains to multiple antibiotics further complicates treatment. NTS disease in the USA is accounted for primarily by serovars belonging to three serogroups (B, C and D). Our overall goal is to develop a broad-spectrum vaccine against these invasive NTS serogroups. We have already developed live oral and conjugate vaccines against Group B {Salmonella enterica subspecies enterica serovar Typhimurium) and D (S. Enteritidis) serovars that can protect against invasive NTS disease with the wild-type homologous pathogen. Although less common than strains of Salmonella Groups B and D, Group C organisms represent a significant proportion of NTS cases, and some Group C serovars (e.g. S. Choleraesuis) are highly invasive. The purpose of this translational research proposal is to develop Salmonella Group C live attenuated and conjugate vaccines. Our central hypothesis is that appropriately engineered attenuated strains of Salmonella enterica Group Cl and C2 serovars can: 1) allow safe, high yield preparation of core-0 polysaccharide (COPS) and flagella protein for making conjugate vaccines, and 2) serve as protective live attenuated vaccines. We will select suitable Salmonella Group Cl and C2 strains and genetically engineer them so that they are attenuated and secrete large amounts of Phase 1 flagellin protein into the supernatant. We will purify COPS and flagellin from these strains and construct COPS-FliC conjugate vaccines using various chemical strategies. These conjugates will be evaluated in adult and aged mice. Live attenuated Salmonella Group Cl and C2 vaccine strains will also be evaluated for their ability to protect adult and aged mice. We will also determine whether gnotobiotic piglets can be protected from invasive disease by S. Choleraesuis conjugate and live oral vaccines. We will ascertain whether NTS vaccines can also protect against gastroenteritis by testing our live attenuated S. Typhimurium vaccine CVD 1931 in the rhesus macaque model of Salmonella gastroenteritis. Finally, we will determine whether a multivalent formulation of live oral or conjugate Group B, C and D Salmonella vaccines can prevent invasive disease caused by Group B, C and D serovars. If we are successful, these results will pave the way for initiating future Phase 1 clinical trials and we will have addressed three ofthe four broad objectives of this multi-center research proposal.

Public Health Relevance

): We will develop Salmonella Group C vaccines that can be formulated with Group B and Group D vaccines that we have already developed, to provide broad spectrum protection against the most common bacteria that cause invasive non-typhoidal Salmonella disease in infants and the elderly.

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)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
United States
Zip Code
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
Ramachandran, Girish; Panda, Aruna; Higginson, Ellen E et al. (2017) Virulence of invasive Salmonella Typhimurium ST313 in animal models of infection. PLoS Negl Trop Dis 11:e0005697
Zhang, Yongrong; Yang, Zhiyong; Gao, Si et al. (2017) The role of purified Clostridium difficile glucosylating toxins in disease pathogenesis utilizing a murine cecum injection model. Anaerobe 48:249-256
Sears, Khandra T; Tennant, Sharon M; Reymann, Mardi K et al. (2017) Bioactive Immune Components of Anti-Diarrheagenic Enterotoxigenic Escherichia coli Hyperimmune Bovine Colostrum Products. Clin Vaccine Immunol 24:
Booth, Jayaum S; Patil, Seema A; Ghazi, Leyla et al. (2017) Systemic and Terminal Ileum Mucosal Immunity Elicited by Oral Immunization With the Ty21a Typhoid Vaccine in Humans. Cell Mol Gastroenterol Hepatol 4:419-437
Salerno-Goncalves, Rosângela; Luo, David; Fresnay, Stephanie et al. (2017) Challenge of Humans with Wild-type Salmonella enterica Serovar Typhi Elicits Changes in the Activation and Homing Characteristics of Mucosal-Associated Invariant T Cells. Front Immunol 8:398
Fresnay, Stephanie; McArthur, Monica A; Magder, Laurence S et al. (2017) Importance of Salmonella Typhi-Responsive CD8+ T Cell Immunity in a Human Typhoid Fever Challenge Model. Front Immunol 8:208
Sztein, Marcelo B (2017) 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 :
Jiang, Bowen; Yu, Hua; Zhang, Yongrong et al. (2017) A Multiparticulate Delivery System for Potential Colonic Targeting Using Bovine Serum Albumin as a Model Protein : Theme: Formulation and Manufacturing of Solid Dosage Forms Guest Editors: Tony Zhou and Tonglei Li. Pharm Res 34:2663-2674

Showing the most recent 10 out of 49 publications