Research Overview

Current

Development of Novel Adjuvants LTA and LTA1, NIH, R01AI114697, 8/2015 – 1/2020, PI

The objective of this proposal is to develop next generation adjuvants based on the A-subunit of the heat-labile enterotoxin from Escherichia coli (LT), including LTA and LTA1. The enterotoxin family of adjuvants are powerful mucosal adjuvants, but have been hindered by major safety concerns in past clinical trials, particularly for intranasal delivery. Our preliminary studies indicate LTA and LTA1 proteins are safe and effective mucosal adjuvants because they can achieve broad mucosal and systemic immunity without the potential safety risks of the parent proteins and high levels of immunogenicity (i.e., anti-LT antibodies).

E112K as a Novel Therapy for Inflammatory Bowel Disease, BMRP, 355407, 12/2015 – 3/2018 (no cost extension), PI

We have discovered novel anti-inflammatory properties in a mutated bacterially-derived protein called E112K. The objective of this proposal is to determine if E112K will be beneficial in mouse models of inflammatory bowel disease (IBD), as a new therapy or prophylaxes.

dmLT Clinical Trials Support, PATH, 06/2014 – 1/2021, PI

Support clinical trial research with dmLT, including stability testing of GMP lots, providing supportive reagents, assessment of candidate vaccine-adjuvant in murine studies, and testing of human samples from ongoing clinical trials for post-vaccination responses.

Development of the Novel Adjuvant LT(R192G/L211A) – dmLT, BAA-NIAID-DAIT-NIH2012146: Adjuvant Development Program, 09/2013 – 09/2018, Co-I (PI J.D. Clements)

The objective of this proposal is to support the development of the novel adjuvant LT(R192G/L211A), or dmLT, toward licensure for human use with potential vaccines against two infectious diseases with significant global health implications, tuberculosis and shigellosis.

The Role of STa in ETEC Pathogenesis, NIH R01, 8/17-7/21, Co-I (PI J.P. Bitoun)

The objective of this project seeks to understand the role of heat-stable enterotoxin, ST, in ETEC pathogenesis.  Our preliminary data indicates that ST suppresses mucosal immune responses to heat-killed ETEC through manipulation of B cell class switching in GALT.  In addition, our data shows that ST binds iron and may link ETEC pathogenesis to nutritional immunity in intestinal tract.

Selected Past

Vaccine efficacy in diabetic and elderly patients, Louisiana Clinical and Translational Science Center Round 3 Pilot Grants, 6/2015 – 12/2016, PI

Our goal is to determine if an individual’s level of inflammation determines their response to vaccination. Old age and diseases, like type-2 diabetes, are characterized as chronic inflammatory conditions and are associated with higher rates of influenza disease and health care costs. While yearly vaccination is recommended, there is a paucity of information comparing vaccination in these high-risk groups and identifying biomarkers that can predict vaccine efficacy. In this pilot proposal, we will examine adult and elderly diabetic and nondiabetic adults for markers of inflammation and vaccine efficacy before and after influenza vaccination.

Supported in part by 1 U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds the Louisiana Clinical and Translational Science Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Physiologic and immunologic consequences of exposure to ETEC enterotoxins, NIH, R21, 8/2014 – 7/2016, Co-I (PI J.D. Clements)

Enterotoxigenic E. coli (ETEC) are a significant cause of morbidity and mortality world-wide, especially in children in developing countries. ETEC cause disease by colonizing the small intestine and producing a heat-labile (LT) and/or heat-stable (ST) enterotoxin. Despite a large fraction of LT/ST dual producing organisms, little is known about consequences of LT and ST interaction. The purpose of this study it to determine the role of LT/ST on accumulation of cyclic nucleotides in T84 cells, innate immune responses in the murine intestine, and adaptive immune responses to ETEC.

Publications

Clements JD, Norton EB. The Mucosal Vaccine Adjuvant LT(R192G/L211A) or dmLT. mSphere. 2018;3(4). Epub 2018/07/27. doi: 10.1128/mSphere.00215-18. PubMed PMID: 30045966.

Norton, E. B., Branco, L.M. Clements, J.D. Evaluating the A-subunit of the heat-labile toxin (LT) as an immunogen and a protective antigen against enterotoxigenic Escherichia coli (ETEC). PLoS One. 2015 Aug 25;10(8):e0136302. doi: 10.1371/journal.pone.0136302. eCollection 2015. PMID: 26305793

Norton E. B., Bauer D.L., Weldon W.C., Oberste M.S., Lawson L.B., Clements J.D. The novel adjuvant dmLT promotes dose sparing, mucosal immunity and longevity of antibody responses to the inactivated polio vaccine in a murine model. Vaccine. 2015;33(16):1909-15. doi: 10.1016/j.vaccine.2015.02.069. PubMed PMID: 25765967.

Read, L.T., Hahn, R.W., Thompson, C.C., Bauer, D.L., Norton, E.B., Clements, J.D. Simultaneous exposure to Escherichia coli heat-labile and heat-stable enterotoxins increases fluid secretion and alters cyclic nucleotide and cytokine production by intestinal epithelial cells. Infect Immun. 2014; 82(12):5308-16. PMID: 25483682

White, J.A., Blum, J.S., Hosken, N.A., Marshak, J.O., Duncan, L., Zhu, C., Norton, E.B., Clements, J.D., Koelle D.M., Chen, D., Lal, M. Serum and mucosal antibody responses to inactivated polio vaccine after sublingual immunization using a thermoresponsive gel delivery system. Hum Vaccin Immunother. 2014 Nov:10(12). PMID: 25483682.

Tomchuck, S.L., Norton, E.B., Garry, R.F., Bunnell, B.A., Morris, C.A., Freytag, L.C., Clements, J.D. Mesenchymal Stem Cells as a Novel Vaccine Platform. Front Cell Infect Microbiol. 2012 Nov 2: 140. PMID: 23162801.

Norton, E. B., L. B. Lawson, Mahdi, Z., Freytag, L.C., Clements, J.D. The A-subunit of Escherichia coli heat-labile enterotoxin functions as a mucosal adjuvant and promotes IgG2a, IgA and Th17 responses to vaccine antigens. Infect Immun. 2012 Jul;80(7):2426-35. PMID: 22526674

Lawson, L.B., Norton, E.B., Clements, J.D. Defending the Mucosa: Adjuvant and Carrier Formulations for Mucosal Immunity. Curr Opin Immunol. 2011 Jun;23(3):414-20. PMID: 21511452.

Cross R.W., Betancourt, A.M., Schur, M.J., Norton, E.B., Roy D, et al. Impact of Primary Influenza Infection on the Immune Response to Secondary Bacterial Infection in Aged Mice. Symposium on viral respiratory disease surveillance. Influenza and Other Respiratory Viruses.2011 May. (Suppl. 1), 195–201.

Norton, E. B., L. B. Lawson, Freytag, L. C., Clements, J.D. 2011. Characterization of a Mutant Escherichia coli Heat-labile Toxin, R192G/L211A, as a Safe and Effective Oral Adjuvant. Clin Vaccine Immunol. 2011 Apr;18(4):546-51. PMID: 21288994.

Norton, E., Clements, J, Voss, T., Freytag, L. Prophylactic Administration of Bacterially Derived Immunomodulators Improves the Outcome of Influenza Virus Infection in a Murine Model. J Virol. 2010 Mar; 84(6):2983-95. PMID: 20053748

Norton, E.B. Evaluation of Vaccine Adjuvants as Immunomodulators in Pulmonary Disease. Dissertation Thesis. 2009.

Norton, E., Archibald, L. K., Nwanyanwu, O. C., Kazembe, P. N., Dobbie, H., Reller B.R., Jarvis, W. R Jason, J. Clinical Predictors of Bloodstream Infections and Mortality in Hospitalized Malawian Children. Pediatr Infect Dis J. 2004 Feb;23(2):145-51. Discussion 151-5. PMID: 14872181

Jason, J., Archibald, L. K., Nwanyanwu, O. C., Kazembe, P. N., Chatt, J. A., Norton, E., Dobbie, H., Jarvis, W. R. Clinical and Immune Impact of Mycobacterium bovis BCG Vaccination Scarring. Infect Immun. 2002 Nov;70(11):6188-95.

For more information, visit Dr. Norton’s MyBibliography page.

Comments are closed.