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-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
Higginson, Ellen E; Simon, Raphael; Tennant, Sharon M (2016) Animal Models for Salmonellosis: Applications in Vaccine Research. Clin Vaccine Immunol 23:746-56
Curtis, Brittany; Grassel, Christen; Laufer, Rachel S et al. (2016) Simple method for purification of enterotoxigenic Escherichia coli fimbriae. Protein Expr Purif 119:130-5
Tennant, Sharon M; Steele, A Duncan; Pasetti, Marcela F (2016) Highlights of the 8th International Conference on Vaccines for Enteric Diseases: the Scottish Encounter To Defeat Diarrheal Diseases. Clin Vaccine Immunol 23:272-81
Zhang, Yongrong; Feng, Hanping (2016) Pathogenic effects of glucosyltransferase from Clostridium difficile toxins. Pathog Dis 74:ftw024
DeLaine, BreOnna C; Wu, Tao; Grassel, Christen L et al. (2016) Characterization of a multicomponent live, attenuated Shigella flexneri vaccine. Pathog Dis 74:
Darton, Thomas C; Jones, Claire; Blohmke, Christoph J et al. (2016) Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a. PLoS Negl Trop Dis 10:e0004926
Yang, Zhiyong; Shi, Lianfa; Yu, Hua et al. (2016) Intravenous adenovirus expressing a multi-specific, single-domain antibody neutralizing TcdA and TcdB protects mice from Clostridium difficile infection. Pathog Dis 74:
Maldarelli, Grace A; Matz, Hanover; Gao, Si et al. (2016) Pilin Vaccination Stimulates Weak Antibody Responses and Provides No Protection in a C57Bl/6 Murine Model of Acute Clostridium difficile Infection. J Vaccines Vaccin 7:
Toapanta, Franklin R; Bernal, Paula J; Fresnay, Stephanie et al. (2016) Oral Challenge with Wild-Type Salmonella Typhi Induces Distinct Changes in B Cell Subsets in Individuals Who Develop Typhoid Disease. PLoS Negl Trop Dis 10:e0004766
Galen, James E; Buskirk, Amanda D; Tennant, Sharon M et al. (2016) Live Attenuated Human Salmonella Vaccine Candidates: Tracking the Pathogen in Natural Infection and Stimulation of Host Immunity. EcoSal Plus 7:

Showing the most recent 10 out of 34 publications