Sean Diehl, Ph.D.

Associate Professor

Training & Education

Dr. Diehl received his Ph.D. in 2003 from The University of Vermont working with Mercedes Rincon studying how CD4+ T helper cells, akin to the Chief Executive Officer of the immune system, respond to cues within the body and enact a management style most effective against that infection. His PhD work on T cells was conducted in mouse models and for postdoctoral research, he shifted focus to human immunology with emphasis on another arm of the immune system: B cells. B cells manufacture antibodies which are exquisitely tailored protein tools critical to controlling infection. He studied how naïve B cells that do not yet make antibodies, become activated (in part by CD4+ T cells) to scale up and develop into antibody-producing cellular factories such as plasmablasts and plasma cells. Alternatively, activated B cells can develop into memory B cells that persist long after infection to provide an institutional memory of those manufactured antibodies to facilitate their rapid remanufacture (or improvement) to protect against a subsequent pathogen encounter. This work in the lab of Dr. Hergen Spits at the University of Amsterdam provided mechanistic insights which formed the groundwork of a new technique that Sean’s lab uses to discover new anti-viral antibodies from patients. This work also directly led to the development of a new antibody (Nirsevimab) that can protect premature infants after one dose for an entire winter season against respiratory syncytial virus (RSV).

Dr. Diehl’s work in the Department of Microbiology and Molecular Genetics encompasses translational and basic research aimed at understanding the human immune response to viral infections, primarily to dengue virus, zika virus, norovirus, and SARS-CoV-2. His goal is to develop novel immune metrics and specific antibody tools that can be used to advance vaccine development and to understand host-pathogen interactions during viral infection or vaccination.  

Research Interests

In my lab we seek to understand how infectious agents engage the human immune system and impart long-term memory. This knowledge is critical to developing better vaccines and to develop better laboratory tests to determine whether vaccine candidates engage the immune system in a way that is likely to lead to protection. The mosquito-borne flaviviruses dengue and zika cause endemic or pandemic disease and long-term sequelae across over 40% of the world’s population and there are no broadly licensed vaccines for either. Our work on dengue and zika immunology draws on an extensive bank of human vaccine clinical trial specimens and natural infection studies in partnership with the Vaccine Testing Center and other collaborators.

More recently we seek to understand how norovirus, a family of viruses for which there is no vaccine and causes significant gastrointestinal illness (vomiting and diarrhea) and hospitalization can skew the infant antibody response towards those that may not offer protection. In March 2020 we implemented broad serological testing for SARS-CoV-2, the virus underlying COVID-19 used to profile hospitalized COVID-19 patients as well as those exposed to the virus but did not require hospitalization. Further work is aimed at identifying novel monoclonal antibodies and T cell responses to the virus.

Techniques we use: human cell culture, virus neutralization, flow cytometry, microscopy, immunoblotting, genomic methods (transcriptomics, PCR, sequencing), molecular cloning.  

Current research projects (Funding/Collaborators)

1) Defining cellular immunogenicity for dengue vaccine formulations (Bill and Melinda Gates Foundation, NIH). 
2) Influence of serostatus on dengue vaccine immunogenicity (NIH)
3) Defining B cell memory to Dengue and Zika and developing potent neutralizing antibodies (CDC and NIH, Collaboration with A. De Silva, University of North Carolina, Chapel Hill).  
4) Transcriptional profiling of DENV virus infection (Joint College of Medicine/Engineering Biomedical Engineering grant with Donna Rizzo and John Hanley from UVM and Sam Scarpino from Northeastern). 
5) Cellular and molecular characterization of dengue-associated rash (Merck).
6) Determinants of Humoral Immunity to Norovirus in Children (NIH, Collaboration with Dr. Sylvia Becker-Dreps at University of North Carolina, Chapel Hill).

 

Diagram showing genetic reprogramming of memory B cells to interrogate human antibody response to infection

Teaching

Courses:
LCOM Foundations of Clinical Science – Lecturer
MMG 320 (Cellular Microbiology) – Lecturer
MLRS310 (Advanced Immunology) – Lecturer
MMG223 (Immunology) – Course Director

Philosophy:
My teaching philosophy is that content is best retained and recalled through high in-class involvement, anchoring to relevant examples, and interactive active learning approaches. In my lectures, I reference cutting-edge research across fields, employ group-oriented case studies, and inspire real-time content adeptness through interactive, online quiz competitions. I try to keep my delivery of the material fun in the hope that this fun will become infectious to students and inspire them to do their best. 

Featured Publications

Graham NR, Whitaker AN, Strother CA, Miles AK, Grier D, McElvany BD, Bruce EA, Poynter ME, Pierce KK, Kirkpatrick BD, Stapleton RD, An G, Botten JW, Crothers JW, Diehl SA* Kinetics and isotype assessment of antibodies targeting the spike protein receptor-binding domain of severe acute respiratory syndrome-coronavirus-2 in COVID-19 patients as a function of age, biological sex and disease severity. Clin. Transl. Immunol. (2020) 9: e1189. *corresponding author 

Graham NG, Eisenhauer P, Diehl SA, Pierce KK, Whitehead SS, Durbin AP, Kirkpatrick BD, Sette A, Weiskopf D, Boyson JE, Botten JW. Rapid Induction and Maintenance of Virus-Specific CD8+ TEMRA and CD4+ TEM Cells Correlates with Complete Protection in a Human Model of Tetravalent Dengue Virus Vaccination and Challenge. Frontiers in Immunology. (2020) 11:479. doi: 10.3389/fimmu.2020.00479. eCollection 2020. PubMed PMID:32265929; PubMed Central PMCID: PMC7105617

Nivarthi UK, Tu HA, Delacruz MJ, Swanstrom J, Patel B, Durbin AP, Whitehead SS, Pierce KK, Kirkpatrick BD, Baric RS, Nguyen N, Emerling DE, de Silva AM# Diehl SA#. Dengue Virus Type 2 Human Infection Model: Longitudinal Analysis of Acute and Convalescent Stage B Cell Responses. EBioMedicine 2019 Mar;41:465-478. doi: 10.1016/j.ebiom.2019.02.060. PMCID: PMC6444124 #co-senior authors. Featured on Technology Networks

Collins M, Tu H, Gimblet-Ochieng, C, Liou AG-J, Jadi R, Metz S, Thomas A, McElvany BD, Davidson E, Doranz B, Reyes Y, Bowman N, Becker-Dreps S, Bucardo F, Lazear H, Diehl SA#, de Silva AM#. The human immune response to primary Zika virus infection is dominated by antibodies recognizing type-specific quaternary structure epitopes on the virion. JCI Insight. Apr 18;4(8). pii: 124588. doi: 10.1172/jci.insight.124588. PMCID: PMC6538335 #co-senior author

Whitehead SS, Durbin AP, Pierce KK, Elwood D, Fraser EJ, Carmolli MP, Tibery CM, Hynes NA, Jo M, Lovchik JM, Larsson CJ, Doty EA, Dickson DM, Luke CJ, Subbarao K, Diehl SA*, and Kirkpatrick BD*. In a Randomized Trial The Live Attenuated Tetravalent Dengue Vaccine TV003 Is Well-Tolerated and Highly Immunogenic in Subjects with Flavivirus Exposure Prior To Vaccination. PLoS Neglected Tropical Diseases. 2017 11(5): e0005584.*co-senior author. PMCID: PMC5436874

Kirkpatrick BD, Whitehead SS, Pierce KK, Tibery CM, Grier PL, Hynes NA, Larsson CJ, Sabundayo BP, Talaat KR, Janiak A, Carmolli MP, Luke CJ, Diehl SA, Durbin AP. The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model. Sci Transl Med. 2016 Mar 16;8(330):330ra36. PubMed PMID: 27089205. NIHMSID: 877588.

Kwakkenbos MJ, Diehl SA*, Yasuda E, Bakker AQ, van Geelen CM, Lukens MV, van Bleek GM, Widjojoatmodjo MN, Bogers WM, Mei H, Radbruch A, Scheeren FA, Spits H, Beaumont T. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming. Nat Med. 2010 16(1):123-8. PMCID: PMC2861345.
*co-first authors

Angelo MA, Grifoni A, O'Rourke PH, Sidney J, Paul S, Peters B, de Silva AD, Phillips E, Mallal S, Diehl SA, Kirkpatrick BD, Whitehead SS, Durbin AP, Sette A, Weiskopf D. Human CD4+ T Cell Responses to an Attenuated Tetravalent Dengue Vaccine Parallel Those Induced by Natural Infection in Magnitude, HLA Restriction, and Antigen Specificity. J Virol. 2017 Feb 14;91(5). pii: e02147-16. PMCID: PMC5309943

Weiskopf D, Angelo MA, Bangs DJ, Sidney J, Paul S, Peters B, de Silva AD, Lindow JC, Diehl SA, Whitehead S, Durbin A, Kirkpatrick B, Sette A. The human CD8+ T cell responses induced by a live attenuated tetravalent dengue vaccine are directed against highly conserved epitopes. J Virol. 2015 Jan;89(1):120-8. doi: 10.1128/JVI.02129-14. Epub 2014 Oct 15. PubMed PMID: 25320311; PubMed Central PMCID: PMC4301095

 

All Diehl publications

Sean Diehl, PhD

Contact Information

Office: Stafford 224B

Phone: 802-656-9860

Email

Lab Team

Benjamin McElvany, Senior Research Analyst 
Nancy Graham, Senior Research Analyst
Huy Tu, PhD, Postdoctoral Associate – Development of humoral immunity to dengue and Zika viruses.
Camilla “Kip” Strother, Graduate Student, Cellular, Molecular and Biomedical Research Program – infant Norovirus immunity and monoclonal antibodies against COVID-19. 
Caleb Buerger, Undergrad research fellow – Ontogeny of cross-reactive dengue antibodies.

Alumni

Tess Solomon, MPH, Undergraduate researcher, currently Policy and Research Associate
Erick McLean, Undergraduate researcher, currently medical student at UVM
Emily Vayda, MD, Undergraduate research fellow, currently Resident, Family Medicine, Maine Medical Center, Portland, ME
Katelyn Roberts, Undergraduate research fellow, Process Development Scientist at Eurofins
Hannah Hatch, Undergraduate research fellow (Nicole J. Ferland award), currently Clinical Researcher Vermont Cancer Center
Dylan Koundakjian, Medical student research fellow– Induction of B cell responses by DENV-infected monocytes.