The goal of this proposal is to construct a vaccine that is broadly protective against multiple enteropathogens of public health importance to the U.S. population. These include Shigella, enterotoxigenic E. coli (ETEC) and the emerging pathogens Shiga toxin producing E. coli (STEC and enteroaggregative E. coli (EAEC). Such a multivalent vaccine would also provide protection against emerging pathogens that have acquired new virulence factors such as the Shiga toxin-expressing EAEC German outbreak strain. These enteropathogens are all Category B risk agents of biodefense concern. A vaccine with broad coverage against this group would be beneficial to multiple segments of the US population, including: 1) adult and child travelers who visit less developed countries where these infections are hyperendemic; 2) children in certain high risk areas of the US; 3) and for mass immunization in the face a natural or deliberate outbreak scenario. Immunization by the mucosal route is an effective method for induction of mucosal and systemic immune responses, believed to be important in protection against these enteropathogens. Our successful completion of 5 attenuated Shigella live vector strains during the Mid- Atlantic RCE (MARCE) funding period, provides the platform for the expression of protective antigens from each enteropathogen. Chromosomal insertion technology and autotransporter-based surface expression of heterologous antigens will ensure stability of vaccine constructs and optimal presentation to the host. In order to confirm the safety, immunogenicity and protective capacity of the multivalent vaccine, we have recruited expert collaborators who have developed innovative, relevant animal models for each component enteropathogen. These studies will constitute preclinical evaluations necessary for advancement to clinical trials. The multivalent vaccine will be tested in the neonatal mouse model in order to assess its utility in the very young thus expanding the potential target population age range. At the completion of these studies, we expect to have completed the construction and testing of a multivalent vaccine consisting of a mixture of live attenuated Shigella strains expressing critical antigens from ETEC, STEC and EAEC that will be broadly protective against enteric infections with these pathogens. The genetic related of these pathogens makes them well suited for grouping in this vaccine strategy that represents an important part of the overall program to develop an Immunoprophylactic Strategy to Control Emerging Enteric Infections.

Public Health Relevance

A vaccine will be developed that is broadly protective against multiple enteropathogens of public health importance to US and global populations including Shigella, STEC, EAEC and ETEC. This multivalent vaccine could also protect against infections with emerging bacterial pathogens which are acquired additional virulence factors.

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
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