Kevin O'Neil Saunders, PhD

Associate Professor in Surgery
Assistant Professor in the Department of Immunology
Assistant Professor in the Department of Molecular Genetics and Microbiology
Member of the Duke Human Vaccine Institute
Campus mail 2 Genome Court, 4074 Medical Science Research Building 2, Durham, NC 27710
Phone (919) 684-1503
Email address kevin.saunders@duke.edu

The Saunders laboratory aims to understand the immunology of HIV-1 antibodies and the molecular biology of their interaction with HIV-1 envelope (Env) glycoprotein. Our overall goal is to develop protective antibody-based vaccines; therefore, the laboratory has two sections–antibody repertoire analysis and immunogen design. Our research premise is that vaccine-elicited antibodies will broadly neutralize HIV-1 if they can bind directly to the host glycans on Env. However, Env glycans are poorly immunogenic and require specific targeting by a vaccine immunogen to elicit an antibody response.

Anti-glycan HIV-1 antibody biology. The laboratory utilizes single B cell PCR to probe the antibody repertoire during natural infection and after vaccination. Using this technique we identified two monoclonal antibodies from HIV Env vaccinated macaques called DH501 and DH502 that bind directly to mannose glycans and to HIV-1 envelope (Env). We have characterized these antibodies using glycan immunoassays, antibody engineering, and x-ray crystallography to define the mechanisms of Env-glycan interaction by these antibodies. Glycan-reactive HIV antibodies are rarely elicited with HIV-1 vaccination; therefore we have studied the ontogeny of DH501 using longitudinal next generation sequencing and reversion of somatic mutations within the antibody variable regions. DH501 and DH502 antibodies are mostly found in the repertoire as IgG2 and IgM isotypes—similar to known natural glycan antibodies. Therefore we are examining whether vaccines mobilize antibodies from the natural glycan pool that affinity mature to interact with HIV-1 envelope. The results of these studies inform us about the similarities and differences between vaccine-induced glycan-reactive antibodies and known broadly neutralizing HIV-1 antibodies from human natural infection. These comparative studies define the molecular biology of glycan-reactive antibodies as well as determine how close current vaccines are to inducing glycan-dependent broadly neutralizing antibodies.

HIV-1 Env immunogen design. The discovery of lineages of broadly neutralizing antibodies in HIV-infected individuals has provided templates for vaccine design. With knowledge of the antibodies we desire to elicit we can engineer the HIV-1 Env to preferentially bind to those antibodies. We discovered that Man9GlcNAc2 is the glycan preferred by early precursors in broadly neutralizing antibody lineages. We translated this finding into a vaccine design strategy that we have termed “glycan learning.” This approach modifies the glycosylation of HIV-1 Env immunogens to be the optimal glycan type for engagement of the precursor antibody of glycan-reactive broadly neutralizing HIV-1 antibody lineages. The Env glycosylation sites and glycan type are then modified on subsequent Env immunogens to select antibodies that are maturing towards a broadly neutralizing phenotype. We have developed cell culture procedures and purification strategies combined with mass spectrometry analyses to create Env immunogens with specific glycosylation profiles. While the overall goal is to elicit protective neutralizing antibodies in vivo, we use these Env antigens in vitro to investigate the biology of B cell receptor engagement. More specifically, we investigate the effects of various immunogen delivery platforms, such as protein or gold nanoparticles, nucleic acid, or recombinant viral vectors on B cell activation.

Taken together, our research program is an interdisciplinary approach to understanding the molecular biology underlying antibody recognition of glycoproteins in order to produce protective vaccines.

Education and Training

  • Ph.D., Duke University, 2010

Publications

Crooks, Ema T., Samantha L. Grimley, Michelle Cully, Keiko Osawa, Gillian Dekkers, Kevin Saunders, Sebastian Rämisch, et al. “Glycoengineering HIV-1 Env creates 'supercharged' and 'hybrid' glycans to increase neutralizing antibody potency, breadth and saturation.” Plos Pathog 14, no. 5 (May 2018): e1007024. https://doi.org/10.1371/journal.ppat.1007024.

PMID
29718999
Full Text

Saunders, Kevin O., Sampa Santra, Robert Parks, Nicole L. Yates, Laura L. Sutherland, Richard M. Scearce, Harikrishnan Balachandran, et al. “Immunogenicity of NYVAC Prime-Protein Boost Human Immunodeficiency Virus Type 1 Envelope Vaccination and Simian-Human Immunodeficiency Virus Challenge of Nonhuman Primates.” J Virol 92, no. 8 (April 15, 2018). https://doi.org/10.1128/JVI.02035-17.

PMID
29437967
Full Text

Saunders, Kevin O., Laurent K. Verkoczy, Chuancang Jiang, Jinsong Zhang, Robert Parks, Haiyan Chen, Max Housman, et al. “Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models.” Cell Rep 21, no. 13 (December 26, 2017): 3681–90. https://doi.org/10.1016/j.celrep.2017.12.028.

PMID
29281818
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Williams, Wilton B., Jinsong Zhang, Chuancang Jiang, Nathan I. Nicely, Daniela Fera, Kan Luo, M Anthony Moody, et al. “Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations.” Nat Commun 8, no. 1 (November 23, 2017): 1732. https://doi.org/10.1038/s41467-017-01336-3.

PMID
29170366
Full Text

Han, Qifeng, Wilton B. Williams, Kevin O. Saunders, Kelly E. Seaton, Kevin J. Wiehe, Nathan Vandergrift, Tarra A. Von Holle, et al. “HIV DNA-Adenovirus Multiclade Envelope Vaccine Induces gp41 Antibody Immunodominance in Rhesus Macaques.” J Virol 91, no. 21 (November 1, 2017). https://doi.org/10.1128/JVI.00923-17.

PMID
28794027
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Bradley, Todd, Justin Pollara, Sampa Santra, Nathan Vandergrift, Srivamshi Pittala, Chris Bailey-Kellogg, Xiaoying Shen, et al. “Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge.” Nat Commun 8 (June 8, 2017): 15711. https://doi.org/10.1038/ncomms15711.

PMID
28593989
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Bonsignori, Mattia, Edward F. Kreider, Daniela Fera, R Ryan Meyerhoff, Todd Bradley, Kevin Wiehe, S Munir Alam, et al. “Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies.” Sci Transl Med 9, no. 381 (March 15, 2017). https://doi.org/10.1126/scitranslmed.aai7514.

PMID
28298420
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Alam, S Munir, Baptiste Aussedat, Yusuf Vohra, R Ryan Meyerhoff, Evan M. Cale, William E. Walkowicz, Nathan A. Radakovich, et al. “Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide.” Sci Transl Med 9, no. 381 (March 15, 2017). https://doi.org/10.1126/scitranslmed.aai7521.

PMID
28298421
Full Text

Saunders, Kevin O., Nathan I. Nicely, Kevin Wiehe, Mattia Bonsignori, R Ryan Meyerhoff, Robert Parks, William E. Walkowicz, et al. “Vaccine Elicitation of High Mannose-Dependent Neutralizing Antibodies against the V3-Glycan Broadly Neutralizing Epitope in Nonhuman Primates.” Cell Rep 18, no. 9 (February 28, 2017): 2175–88. https://doi.org/10.1016/j.celrep.2017.02.003.

PMID
28249163
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Easterhoff, David, M Anthony Moody, Daniela Fera, Hao Cheng, Margaret Ackerman, Kevin Wiehe, Kevin O. Saunders, et al. “Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial.” Plos Pathog 13, no. 2 (February 2017): e1006182. https://doi.org/10.1371/journal.ppat.1006182.

PMID
28235027
Full Text

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