Research Overview

Current Projects

(1) Develop dmLT and LTA1 Adjuvant to promote protective immunity to vaccines. We work on unique Th1/Th17/Th2-promoting vaccine adjuvants dmLT or LTA1 adjuvants to enable generation of mucosal immunity or for mucosally delivered vaccines. Our work with dmLT has continued ever since Dr. Norton’s post-doctoral fellowship with John Clements and with enterotoxigenic E. coli (ETEC), polio, tuberculosis and other vaccines. In addition, our laboratory has also pioneered the use of LTA1 for intranasal use in flu, klebsiella and opioid vaccines. We have also demonstrated improved safety of LTA1 compared with native enterotoxin. Our work continues to promote these adjuvants, supporting existing vaccines in pre-clinica/clinical development, test new formulation to harness the unique properties of these adjuvants, and collaborate with numerous other national and international scientists on this work. As part of this, we aim to freely share LT, dmLT, LTA1 etc. associated proteins with other laboratories.

(2) Investigate the mechanisms of LT-based proteins on development of immunity in vaccines and therapeutics. We recently observed that neither dmLT or LTA1 signal through PKA activation. In addition, we have used active site mutant E112K to prevent the stimulation of immunity and inflammation (as a novel inflammatory bowel disease (IBD) therapeutic), likely through interactions with the host ARF protein. In the ongoing studies, we plan to define how these proteins stimulate immunity, which key signals are involved and which cells. We are using targeted genetic depletion models to perform these studies as well as comparisons with novel mutant LT proteins. This research aims to: (1) provide mechanistic incite that can be used to support dmLT vaccines in clinical trials or pre-clinical studies, (2) understand LT-based protein interaction on immunity to design next generation adjuvants and therapeutics, (3) provide context to how LT protein during ETEC infection shapes memory responses.

(3)Understand factors regulating development of protective immunity. Humans have a wide-variety of responses to infection or vaccination. The drivers of what shapes immunity is not always clear. Many of our pre-clinical  studies are limited in their evaluation of host factors that play major roles in vaccine efficacy or immunity to infections, including age, co-morbidities (e.g. diabetes, cancer), and inflammation. Our recent studies with flu have confirmed that both baseline levels of inflammation and diabetes alter responses to flu infection and vaccination (Baudier et al, in preparation). With the SARS-CoV-2 pandemic these knowledge deficiencies are even clearer. We plan to tackle these questions by evaluating human samples for protective immunity to SARS-CoV-2 infection and also investigate this immunity within context of vaccination to influenza, RSV, or SARS-CoV-2 through a NIH funded projects.

Current or Recent Funding Sources: 

Adjuvant or ETEC Research: NIH/NIAID: 5R01AI166682-03, NIH/NIAID: 75N93022C00056-0-9999-1, NIH/NIAID: 75N93023C00045-0-9999-1, PATH Vaccine Solutions

Immunity during Infection/Vaccination: NIH 5R01HL061007-16 (PI-Piedimonte); NIH/NCI Seronet: 1U54CA260581-01 Tulane University COVID Antibody and Immunity Network (TUCAIN); LA CaTS/REACHNET

Publications

Lauritsen CJ, Trinh IV, Desai SP, Clancey E, Murrell AE, Rambaran S, Chandra S, Elliott DH, Smira AR, Mo Z, Stone AE, Agbodji A, Dugas CM, Satou R, Pridjian G, Longo S, Ley SH, Robinson JE, Norton EB, Piedimonte G, Gunn BM. Passive antibody transfer from pregnant women to their fetus are maximized after SARS-CoV-2 vaccination irrespective of prior infection. J Allergy Clin Immunol Glob. 2024 Feb;3(1):100189. doi: 10.1016/j.jacig.2023.100189. eCollection 2024 Feb. PubMed PMID: 38268538; PubMed Central PMCID: PMC10805668.

Harrison MAA, Morris SL, Rudman GA, Rittenhouse DJ, Monk CH, Sakamuri SSVP, Mehedi Hasan M, Shamima Khatun M, Wang H, Garfinkel LP, Norton EB, Kim S, Kolls JK, Michal Jazwinski S, Mostany R, Katakam PVG, Engler-Chiurazzi EB, Zwezdaryk KJ. Intermittent cytomegalovirus infection alters neurobiological metabolism and induces cognitive deficits in mice. Brain Behav Immun. 2024 Jan 3;117:36-50. doi: 10.1016/j.bbi.2023.12.033. [Epub ahead of print] PubMed PMID: 38182037.

Zhang B, Chen S, Yin X, McBride CD, Gertie JA, Yurieva M, Bielecka AA, Hoffmann B, Travis Hinson J, Grassmann J, Xu L, Siniscalco ER, Soldatenko A, Hoyt L, Joseph J, Norton EB, Uthaman G, Palm NW, Liu E, Eisenbarth SC, Williams A. Metabolic fitness of IgA(+) plasma cells in the gut requires DOCK8. Mucosal Immunol. 2023 Dec 28;. doi: 10.1016/j.mucimm.2023.12.001. [Epub ahead of print] PubMed PMID: 38159726.

Shafieichaharberoud F, Lang S, Whalen C, Rivera Quiles C, Purcell L, Talbot C, Wang P, Norton EB, Mazei-Robison M, Sulima A, Jacobson AE, Rice KC, Matyas GR, Huang X. Enhancing Protective Antibodies against Opioids through Antigen Display on Virus-like Particles. Bioconjug Chem. 2023 Dec 19;. doi: 10.1021/acs.bioconjchem.3c00415. [Epub ahead of print] PubMed PMID: 38113481.

Trinh IV, Desai SP, Ley SH, Mo Z, Sato R, Pridjian GC, Longo SA, Shaffer JG, Robinson JE, Norton EB, Piedimonte G. Prenatal Infection by Respiratory Viruses Is Associated With Immuno-Inflammatory Responses in the Fetus. Am J Respir Crit Care Med. 2023 Dec 5;. doi: 10.1164/rccm.202308-1461OC. [Epub ahead of print] PubMed PMID: 38051928.

Crothers JW, Norton EB. Recent advances in enterotoxin vaccine adjuvants. Curr Opin Immunol. 2023 Dec;85:102398. doi: 10.1016/j.coi.2023.102398. Epub 2023 Nov 16. Review. PubMed PMID: 37976963.

Landry SJ, Mettu RR, Kolls JK, Aberle JH, Norton E, Zwezdaryk K, Robinson J. Structural Framework for Analysis of CD4+ T-Cell Epitope Dominance in Viral Fusion Proteins. Biochemistry. 2023 Sep 5;62(17):2517-2529. doi: 10.1021/acs.biochem.3c00335. Epub 2023 Aug 9. Review. PubMed PMID: 37554055; PubMed Central PMCID: PMC10483696.

Stone AE, Rambaran S, Trinh IV, Estrada M, Jarand CW, Williams BS, Murrell AE, Huerter CM, Bai W, Palani S, Nakanishi Y, Laird RM, Poly FM, Reed WF, White JA, Norton EB. Route and antigen shape immunity to dmLT-adjuvanted vaccines to a greater extent than biochemical stress or formulation excipients. Vaccine. 2023 Feb 24;41(9):1589-1601. doi: 10.1016/j.vaccine.2023.01.033. Epub 2023 Jan 31. PubMed PMID: 36732163; PubMed Central PMCID: PMC10308557.

Estrada MR, Bzami A, Norton EB, White JA. Identifying a stable bulk dmLT adjuvant formulation at a clinically relevant concentration. Vaccine. 2023 Feb 10;41(7):1362-1367. doi: 10.1016/j.vaccine.2023.01.005. Epub 2023 Jan 17. PubMed PMID: 36658044; PubMed Central PMCID: PMC9932622.

Ning B, Chandra S, Rosen J, Multala E, Argrave M, Pierson L, Trinh I, Simone B, Escarra MD, Drury S, Zwezdaryk KJ, Norton E, Lyon CJ, Hu T. Evaluation of SARS-CoV-2-Specific T-Cell Activation with a Rapid On-Chip IGRA. ACS Nano. 2023 Jan 3;17(2):1206-16. doi: 10.1021/acsnano.2c09018. [Epub ahead of print] PubMed PMID: 36595218; PubMed Central PMCID: PMC9878992.

Kosten TR, Haile CN, Domingo CB, Norton EB. Anti-Cocaine IgA Rather Than IgG Mediates Vaccine Protection from Cocaine Use. Pharmaceutics. 2022 Nov 3;14(11). doi: 10.3390/pharmaceutics14112368. PubMed PMID: 36365186; PubMed Central PMCID: PMC9697488.

Haile CN, Baker MD, Sanchez SA, Lopez Arteaga CA, Duddupudi AL, Cuny GD, Norton EB, Kosten TR, Kosten TA. An Immunconjugate Vaccine Alters Distribution and Reduces the Antinociceptive, Behavioral and Physiological Effects of Fentanyl in Male and Female Rats. Pharmaceutics. 2022 Oct 26;14(11). doi: 10.3390/pharmaceutics14112290. PubMed PMID: 36365109; PubMed Central PMCID: PMC9694531.

Seifert SN, Bai S, Fawcett S, Norton EB, Zwezdaryk KJ, Robinson J, Gunn B, Letko M. An ACE2-dependent Sarbecovirus in Russian bats is resistant to SARS-CoV-2 vaccines. PLoS Pathog. 2022 Sep;18(9):e1010828. doi: 10.1371/journal.ppat.1010828. eCollection 2022 Sep. PubMed PMID: 36136995; PubMed Central PMCID: PMC9498966.

Bucşan AN, Veatch A, Singh DK, Akter S, Golden NA, Kirkpatrick M, Threeton B, Moodley C, Ahmed M, Doyle LA, Russell-Lodrigue K, Norton EB, Didier PJ, Roy CJ, Abramovitch RB, Mehra S, Khader SA, Kaushal D. Response to Hypoxia and the Ensuing Dysregulation of Inflammation Impacts Mycobacterium tuberculosis Pathogenicity. Am J Respir Crit Care Med. 2022 Jul 1;206(1):94-104. doi: 10.1164/rccm.202112-2747OC. PubMed PMID: 35412961; PubMed Central PMCID: PMC9718519.

Crothers JW, Ross Colgate E, Cowan KJ, Dickson DM, Walsh M, Carmolli M, Wright PF, Norton EB, Kirkpatrick BD. Intradermal fractional-dose inactivated polio vaccine (fIPV) adjuvanted with double mutant Enterotoxigenic Escherichia coli heat labile toxin (dmLT) is well-tolerated and augments a systemic immune response to all three poliovirus serotypes in a randomized placebo-controlled trial. Vaccine. 2022 Apr 26;40(19):2705-2713. doi: 10.1016/j.vaccine.2022.03.056. Epub 2022 Mar 30. PubMed PMID: 35367069; PubMed Central PMCID: PMC9024222.

Dietrich ML, Norton EB, Elliott D, Smira AR, Raviv O, Sasson DJ, Monk CH, Michael ML, Rogers N, Rouelle JA, Bond NG, Aime-Marcelin K, Prystowsky A, Kemnitz R, Sarma A, Himmelfarb ST, Sharma N, Stone AE, Craver R, Lindrose AR, Smitley LA, Uddo RB, Myers L, Drury SS, Schieffelin JS, Robinson JE, Zwezdaryk KJ. SARS-CoV-2 seroprevalence rates of children seeking medical care in Louisiana during the state stay at home order. J Clin Virol Plus. 2021 Dec;1(4):100047. doi: 10.1016/j.jcvp.2021.100047. Epub 2021 Nov 14. PubMed PMID: 35262027; PubMed Central PMCID: PMC8590598.

Combs JA, Monk CH, Harrison MAA, Norton EB, Morris CA, Sullivan DE, Zwezdaryk KJ. Inhibiting cytomegalovirus replication through targeting the host electron transport chain. Antiviral Res. 2021 Oct;194:105159. doi: 10.1016/j.antiviral.2021.105159. Epub 2021 Aug 11. PubMed PMID: 34390771; PubMed Central PMCID: PMC8446325.

Iwanaga N, Chen K, Yang H, Lu S, Hoffmann JP, Wanek A, McCombs JE, Song K, Rangel-Moreno J, Norton EB, Kolls JK. Vaccine-driven lung TRM cells provide immunity against Klebsiella via fibroblast IL-17R signaling. Sci Immunol. 2021 Sep 10;6(63):eabf1198. doi: 10.1126/sciimmunol.abf1198. Epub 2021 Sep 10. PubMed PMID: 34516780; PubMed Central PMCID: PMC8796208.

Schieffelin JS, Norton EB, Kolls JK. What should define a SARS-CoV-2 “breakthrough” infection?. J Clin Invest. 2021 Jun 15;131(12). doi: 10.1172/JCI151186. PubMed PMID: 33974565; PubMed Central PMCID: PMC8203469.

Stone AE, Scheuermann SE, Haile CN, Cuny GD, Velasquez ML, Linhuber JP, Duddupudi AL, Vigliaturo JR, Pravetoni M, Kosten TA, Kosten TR, Norton EB. Fentanyl conjugate vaccine by injected or mucosal delivery with dmLT or LTA1 adjuvants implicates IgA in protection from drug challenge. NPJ Vaccines. 2021 May 13;6(1):69. doi: 10.1038/s41541-021-00329-0. PubMed PMID: 33986280.

Huang Z, Ning B, Yang HS, Youngquist BM, Niu A, Lyon CJ, Beddingfield BJ, Fears AC, Monk CH, Murrell AE, Bilton SJ, Linhuber JP, Norton EB, Dietrich ML, Yee JK, Lai W, Scott JW, Yin XM, Rappaport J, Robinson JE, Saba NS, Roy CJ, Zwezdaryk KJ, Zhao Z, Hu TY. Sensitive tracking of circulating viral RNA through all stages of SARS-CoV-2 infection. J Clin Invest. 2021 Feb 9;. doi: 10.1172/JCI146031. [Epub ahead of print] PubMed PMID: 33561010.

Motyka NI, Stewart SR, Hollifield IE, Kyllo TR, Mansfield JA, Norton EB, Clements JD, Bitoun JP. Elevated Extracellular cGMP Produced after Exposure to Enterotoxigenic Escherichia coli (ETEC) Heat-Stable Toxin (ST) Induces Epithelial IL-33 Release and Alters Intestinal Immunity. Infect Immun. 2021 Jan 11;. doi: 10.1128/IAI.00707-20. [Epub ahead of print] PubMed PMID: 33431701.

Baudier RL, Zwezdaryk KJ, Czarny-Ratajczak M, Kodroff LH, Sullivan DE, Norton EB. Unique Transcriptome Changes in Peripheral B Cells Revealed by Comparing Age Groups From Naive or Vaccinated Mice, Including snoRNA and Cdkn2a. J Gerontol A Biol Sci Med Sci. 2020 Nov 13;75(12):2326-2332. doi: 10.1093/gerona/glaa165. PubMed PMID: 32609344; PubMed Central PMCID: PMC7759738.

Liu S, Liu F, Zhang B, Yan P, Rowan BG, Abdel-Mageed AB, Steele C, Jazwinski SM, Moroz K, Norton EB, Wang A, Myers L, Sartor O, Zhang Q. CD4⁺ T helper 17 cell response of aged mice promotes prostate cancer cell migration and invasion. 2020 Jul;80(10):764-776. doi: 10.1002/pros.23990. Epub 2020 May 1. PubMed PMID: 32356608; PubMed Central PMCID: PMC7310589.

Valli E, Baudier RL, Harriett AJ, Norton EB. LTA1 and dmLT enterotoxin-based proteins activate antigen-presenting cells independent of PKA and despite distinct cell entry mechanisms. PLoS One. 2020;15(1):e0227047. doi: 10.1371/journal.pone.0227047. eCollection 2020. PubMed PMID: 31929548; PubMed Central PMCID: PMC6957164.

Combs JA, Norton EB, Saifudeen ZR, Bentrup KHZ, Katakam PV, Morris CA, Myers L, Kaur A, Sullivan DE, Zwezdaryk KJ. Human Cytomegalovirus Alters Host Cell Mitochondrial Function during Acute Infection. J Virol. 2020 Jan 6;94(2). doi: 10.1128/JVI.01183-19. Print 2020 Jan 6. PubMed PMID: 31694945; PubMed Central PMCID: PMC6955246.

Valli E, Harriett AJ, Nowakowska MK, Baudier RL, Provosty WB, McSween Z, Lawson LB, Nakanishi Y, Norton EB. LTA1 is a safe, intranasal enterotoxin-based adjuvant that improves vaccine protection against influenza in young, old and B-cell-depleted (μMT) mice. Sci Rep. 2019 Oct 22;9(1):15128. doi: 10.1038/s41598-019-51356-w. PubMed PMID: 31641151; PubMed Central PMCID: PMC6805908.

Maciel M Jr, Bauer D, Baudier RL, Bitoun J, Clements JD, Poole ST, Smith MA, Kaminski RW, Savarino SJ, Norton EB. Intradermal or Sublingual Delivery and Heat-Labile Enterotoxin Proteins Shape Immunologic Responses to a CFA/I Fimbria-Derived Subunit Antigen Vaccine against Enterotoxigenic Escherichia coli. Infect Immun. 2019 Nov;87(11). doi: 10.1128/IAI.00460-19. Print 2019 Nov. PubMed PMID: 31427449; PubMed Central PMCID: PMC6803349.

Norton EB. Altered responses to pneumococcal vaccination in an elderly diabetic Japanese vaccine trial: The risk of concurrent vaccination strategies. J Diabetes Complications. 2019 Mar;33(3):189-190. doi: 10.1016/j.jdiacomp.2018.12.007. Epub 2018 Dec 21. PubMed PMID: 30651178.

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 EB, Bauer DL, Weldon WC, Oberste MS, Lawson LB, Clements JD. 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 Apr 15;33(16):1909-15. doi: 10.1016/j.vaccine.2015.02.069. Epub 2015 Mar 9. 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.