Enteric pathogens cause disease among individuals living in both developing and industrialized countries, with some pathogens being universal, while others are largely restricted to certain settings. Certain enteric pathogens are epidemiologically emerging or re-emerging. Travelers from industrialized countries who visit developing countries form a special risk group that bridges the two broad ecologies. Finally, a few enteric pathogens are of special interest from the civilian biodefense perspective, as they have been used by nefarious individuals to promulgate bioterror (non-typhoidal Salmonella), or have properties that suit them to such a purpose (Shigella dysenteriae 1). The five Projects described in this Enteric Center for Excellence in Translation Research (""""""""Enteric CETR"""""""") proposal, bonded by the theme """"""""Immunoprophylactic Strategy to Control Emerging Enteric Infections"""""""", will undertake translational research towards developing products to prevent enteric disease caused by several important bacterial and protozoal pathogens, including: the enteric fever Salmonella serovars S. Typhi, S. Paratyphi A and S. Paratyphi B (Project 1);Clostridium difficile (Project 2);Shigella, enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAEC) and Shiga toxin-producing enterohemorrhagic E. coli (EHEC) diarrheal pathogens (Project 3);non-typhoidal Salmonella serovars that cause invasive disease and/or gastroenteritis (emphasizing group C serovars) (Project 4);the protozoan species Cryptosporidium hominis and C. parvum (Project 5). Whereas each pathogen represents an important public health priority, only one, S. Typhi, already has licensed vaccines to prevent disease and those are not ideal. Three projects intend to progress new vaccine candidates to the point where Investigational New Drug Applications (IND) could be prepared to initiate Phase 1 clinical trials. These include: i) a Shigella live vector vaccine expressing protective antigens to prevent clinical illness caused by several pathotypes of diarrhea-causing Escherichia coli (Project 3);ii) Core-O polysaccharide-flagellin conjugate parenteral vaccines, as well as engineered recombinant attenuated strains, to prevent invasive disease caused by non-typhoidal serovars of Salmonella Group C1 &C2 (Project 4);iii) a vaccine based on proteins from C. hominis and C. parvum sporozoites;iv) a bivalent adjuvanted cTxAB toxoid vaccine to prevent recurrent C. difficile disease (Project 2). We will also investigate a unique passive antibody approach to prevent C. difficile disease (Project 2). Finally, Project 1 aims to explain the cross protection observed in large-scale field trials wherein oral immunization with live S. Typhi vaccine strain Ty21a conferred cross protection against S. Paratyphi B, whereas no protection was afforded against S. Paratyphi A. Most projects will utilize innovative animal models including senescent mouse models (to explore how aging influences immune response to vaccines) and the gnotobiotic piglet model. All projects include collaborations of investigators across multiple institutions of he consortium. The Enteric CETR PL/PD is highly experienced in translational research and vaccine product development.

Public Health Relevance

So-called enteric infections, which include different types of diarrheal illnesses, dysentery (bloody diarrhea) and typhoid and paratyphoid fevers, represent unsolved clinical problems affecting persons of all ages (but particularly young children and the elderly) in both advanced countries like the USA and among underprivileged populations living in developing countries. A small number of enteric disease-causing microorganisms (germs), most of them resistant to antibiotics, are collectively responsible for a disproportionate amount of enteric disease, and several are the targets of focused research to develop new vaccines and other tools to prevent these infections. If the interactive, multi-disciplinary, multi-institutiona Enteric Center of Excellence for Translational Research that we are proposing is successful, it will accelerate the development of innovative, safe, and effective vaccines and other interventions to prevent some of the most devastating, worrisome, difficult to treat enteric infections, thereby potentially resulting in hundreds of thousands of cases averted and thousands of lives saved both in the USA and worldwide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109776-01
Application #
8642251
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Program Officer
Parker, Tina M
Project Start
2014-03-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$4,894,397
Indirect Cost
$1,213,595
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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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:
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
Bolick, David T; Mayneris-Perxachs, Jordi; Medlock, Greg L et al. (2017) Increased Urinary Trimethylamine N-Oxide Following Cryptosporidium Infection and Protein Malnutrition Independent of Microbiome Effects. J Infect Dis 216:64-71

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