Clostridium difficile infection (CDI) has become a major emerging cause of morbidity and mortality among hospitalized patients since the epidemics of hypervirulent and antibiotic-resistant strains began in the early 2000s. It is therefore important to develop new preventions/treatments to counteract the rapid increase in the incidence of CDI. While standard treatments with antibiotics are not effective resulting in high rates of relapse, animal and clinical studies have unambiguously demonstrated that antitoxin antibodies are protective against both primary and recurrent CDI. Our goal is to develop novel immunoprophylaxes against both primary and recurrent CDI in aged high-risk populations. In this proposal we aim to exploit two novel compounds (ABBA and cTxAB) developed in this lab: 1) ABBA is a single tetra-specific binding agent consisting of four distinct neutralizing VHH monomers (two against TcdA and two against TcdB); and 2) cTxAB is an atoxic, clostridial toxin-like chimeric vaccine for which a product development plan (PDP) toward clinical trials is currently being developed under NIH funding. We have already demonstrated potent efficacy of ABBA against fulminant CDI in mice. We will further optimize and finalize its delivery strategies in this project. To reduce potential immunogenicity and increase the serum half-life of ABBA for systemic administration, we will generate ABBA-Fc fusions and humanized ABBA-lgGIs without compromising its superior affinity to toxins and neutralizing activity. In addition, we will develop a colonic delivery system for intestinal delivery of ABBA. The lead compounds generated for systemic and oral deliveries will be evaluated in a hamster fulminant CDI model as well as in gnotobiotic piglets colonized with human intestinal flora. Moreover, we will combine the passive ABBA immunization with active cTxAB vaccination and evaluate protection against both primary and recurrent CDI in relevant immunosenescent mouse models. Our ultimate goal is to develop novel immunoprophylaxes and combinations of active and passive immunizations that we wish to prevent against both immediate and longer term CDI threats in aged patients with high risk of developing this debilitating disease. This project will help to achieve the broad objective ofthe entire CETR proposal and to address the hypothesis that we can translate promising immunoprophylactic candidate products being tested in relevant immunosenescent animal models into immune preventions against important enteric pathogens for which the ultimate human targets are elderly subjects.

Public Health Relevance

Clostridium difficile infection (CDI) is a major emerging cause of morbidity and mortality among hospitalized elderly patients. This project will optimize and finalize delivery strategies for a potent multi-specific antibody developed in this lab and combine passive and active immunizations in order to prevent both immediate and longer term CDI threats in aged patients with high risk of developing this debilitating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI109776-05
Application #
9447102
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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