Vaccination is one of the most successful and cost-effective ways of preventing infectious disease. The development of effective vaccines for infections of the gastrointestinal tract however has been disappointing. The need for these vaccines is crucial since diarrheal diseases due to infectious agents of the gut are the second leading infectious cause of death in infants and young children world wide. Some of the Infectious agents that cause diarrheal diseases include rotavirus, pathogenic Escherichia coli, Shigella spp., Salmonella spp., Cryptosporidium pan/urn, Entamoeba histolytica, and Vibrio cholera. The reason for the lack of suitable vaccines for enteric pathogens is the lack of an effective adjuvant that can be delivered orally with the vaccine to increase its potency at stimulating an immune response. Most experimental oral adjuvants are ineffective or maintain some degree of toxicity. To address this problem, we propose to couple synthetic peptides from enteric pathogens to a safe and stable adjuvant, aluminum oxide nanoparticles for oral immunization. The peptides will be coupled to the nanoparticles in a way that preserves their native conformation in order to optimize the immune response to recognize the native pathogen. Since very few small animal models of enteric disease and immunity exist, we will use the human pathogen Helicobacter pylori (H. pylori) to infect the mouse gastric mucosa and we will test this technology by 1) Identifying epitopes on H. pylori CagL that are crucial for binding of the bacteria to host cells using an antibody blocking assay with human cell lines, 2) Testing the ability of those CagL epitopes, coupled to aluminum oxide nanoparticles, to induce protective immunity when delivered to mice prior to challenge, 3) Testing the ability of those CagL epitopes, coupled to aluminum oxide nanoparticles, to induce antibodies that block pathogenic and carcinogenic events due to H. pylori infection, and 4) Evaluating the antibody response of infected human subjects to determine if these blocking antibodies are induced by natural infection in order to determine if the induction of these antibodies by vaccination would be beneficial to human patients. A reduction of infection, inflammation, or carcinogenesis in the H. pylori model by immunization with stable, targeted peptide epitopes coupled to nanoparticles would provide compelling evidence for subsequent applications against other enteric bacterial infections in humans that induce significant world wide morbidity and mortality.

Public Health Relevance

Infections of the gastrointestinal tract cause serious diarrheal diseases that are the second leading cause of death due to infection world wide. Few vaccines exist for oral immunization to protect against such pathogens. The technology for generating stable peptide vaccines coupled to a safe effective carrier vehicle would help reduce or eliminate significant morbidity and mortality due to infectious diarrheal diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-KS-I)
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University of Maryland Baltimore
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McArthur, Monica A; Chen, Wilbur H; Magder, Laurence et al. (2017) Impact of CD4+ T Cell Responses on Clinical Outcome following Oral Administration of Wild-Type Enterotoxigenic Escherichia coli in Humans. PLoS Negl Trop Dis 11:e0005291
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
Arevalillo, Jorge M; Sztein, Marcelo B; Kotloff, Karen L et al. (2017) Identification of immune correlates of protection in Shigella infection by application of machine learning. J Biomed Inform 74:1-9
Wahid, Rezwanul; Fresnay, Stephanie; Levine, Myron M et al. (2016) Cross-reactive multifunctional CD4+ T cell responses against Salmonella enterica serovars Typhi, Paratyphi A and Paratyphi B in humans following immunization with live oral typhoid vaccine Ty21a. Clin Immunol 173:87-95
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
Salerno-Goncalves, R; Safavie, F; Fasano, A et al. (2016) Free and complexed-secretory immunoglobulin A triggers distinct intestinal epithelial cell responses. Clin Exp Immunol 185:338-47
Cong, Yu; McArthur, Monica A; Cohen, Melanie et al. (2016) Characterization of Yellow Fever Virus Infection of Human and Non-human Primate Antigen Presenting Cells and Their Interaction with CD4+ T Cells. PLoS Negl Trop Dis 10:e0004709
Blohmke, Christoph J; Darton, Thomas C; Jones, Claire et al. (2016) Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever. J Exp Med 213:1061-77

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